Pyridine-2-amides useful as CB2 agonists

ABSTRACT

The invention relates to CB2 agonists of formula (I) wherein R 1  to R 4  are defined as in the description and in the claims. The compound of formula (I) can be used as a medicament.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a 371 application of International Application No.PCT/EP2013/075443, filed on Dec. 4, 2013, which claims priority toEuropean Patent Application No. 12196032.2, filed on Dec. 7, 2012, theentire contents of which are incorporated herein by reference.

The present invention relates to organic compounds useful for therapyand/or prophylaxis in a mammal, and in particular to compounds that arepreferential agonists of the Cannabinoid Receptor 2.

The invention relates in particular to a compound of formula (I)

wherein

-   -   R¹ is cycloalkylalkoxy, halophenyl, tetrahydrofuranylalkoxy,        halophenylalkyl, haloalkyloxy, alkylsulfonyl,        tetrahydropyranylalkoxy or halogen;    -   R² is alkyl, pyrrolidinyl, cycloalkyl, haloazetidinyl,        haloalkyl, cycloalkylalkoxy, haloalkyloxy, halocycloalkyl,        hydroxycycloalkyl or halooxetanyl;    -   one of R³ and R⁴ is alkyl, cycloalkyl, haloalkyl or hydroxyalkyl        and the other one is alkyl, alkyloxyalkyl,        (haloazetidinyl)(cycloalkyloxy)pyridinylcarbonyloxyalkyl,        haloalkylcycloalkyl, hydroxyalkyl, phenylalkyl,        alkoxycarbonylalkyl, carboxyalkyl, alkylaminocarbonylalkyl,        (alkyloxadiazolyl)(cycloalkylalkyl)alkyl,        (alkyloxadiazolyl)(cycloalkyl)alkyl, pyridazinylalkyl,        aminocarbonylalkyl, alkyloxadiazolylalkyl, alkyltetrazolylalkyl,        formyl, phenyl, dialkylpyrazolyl, alkylcarbonylpiperidinyl or        cycloalkylalkyl;    -   or R³ and R⁴ together with the nitrogen atom to which they are        attached form heterocyclyl or substituted heterocyclyl;    -   wherein heterocyclyl is 6-oxa-1-aza-spiro[3.3]heptyl,        oxazolidinyl, morpholinyl, pyrrolidinyl, piperazinyl,        2-oxa-5-aza-spiro[3.4]octyl, piperidinyl,        6-aza-bicyclo[3.2.1.]octyl, imidazolidinyl,        4-aza-spiro[2.4]heptyl, 2-aza-bicyclo[2.2.1]heptyl,        2-thia-5-aza-bicyclo[2.2.1]heptyl,        2,5-diazabicyclo[2.2.1]heptyl, 2-oxa-5-aza-bicyclo[2.2.1]heptyl,        hexahydrofuro[2,3-c]pyrrolyl, 2-thia-6-aza-spiro[3.3]heptyl,        1,8-diaza-spiro[4.5]decyl, 1-oxa-7-aza-spiro[4.4]nonyl,        5-oxa-2-aza-spiro[3.4]octyl, 8-oxa-3-aza-bicyclo[3.2.1]octyl,        3-oxa-8-aza-bicyclo[3.2.1]octyl, thiomorpholinyl, thiazolidinyl,        5-aza-spiro[3.4]octyl, azetidinyl, 5-aza-spiro[2.4]heptyl,        3-aza-bicyclo[3.1.0]hexyl or 5-aza-spiro[2.4]heptyl,        1,3,3a,4,6,6a-hexahydrofuro[3,4-c]pyrrolyl; and    -   wherein substituted heterocyclyl is heterocyclyl substituted        with one to four substituents independently selected from alkyl,        oxo, hydroxyl, carboxyl, alkylcarbonylamino, alkyloxyalkyl,        hydroxyalkyl, aminocarbonyl, halogen, phenylalkyl, phenyl,        alkoxycarbonyl, cycloalkylalkyl, phenylalkoxycarbonyl,        cycloalkyl, halohydroxyalkyl and haloalkyl;    -   provided that R³ and R⁴ together with the nitrogen atom to which        they are attached don't form unsubstituted piperidinyl,        unsubstituted thiomorpholinyl or hydroxyalkylpyrrolidinyl;    -   or a pharmaceutically acceptable salt or ester thereof.

The compound of formula (I) is particularly useful in the treatment orprophylaxis of e.g. pain, atherosclerosis, age-related maculardegeneration, diabetic retinopathy, glaucoma, retinal vein occlusion,retinopathy of prematurity, ocular ischemic syndrome, geographicatrophy, diabetes mellitus, inflammation, inflammatory bowel disease,ischemia-reperfusion injury, acute liver failure, liver fibrosis, lungfibrosis, kidney fibrosis, systemic fibrosis, acute allograft rejection,chronic allograft nephropathy, diabetic nephropathy,glomerulonephropathy, cardiomyopathy, heart failure, myocardialischemia, myocardial infarction, systemic sclerosis, thermal injury,burning, hypertrophic scars, keloids, gingivitis pyrexia, livercirrhosis or tumors, regulation of bone mass, neurodegeneration,amyotrophic lateral sclerosis, stroke, transient ischemic attack oruveitis.

The compound of formula (I) is in particular useful in the treatment orprophylaxis of diabetic retinopathy, retinal vein occlusion or uveitis.

The cannabinoid receptors are a class of cell membrane receptorsbelonging to the G protein-coupled receptor superfamily. There arecurrently two known subtypes, termed Cannabinoid Receptor 1 (CB1) andCannabinoid Receptor 2 (CB2). The CB1 receptor is mainly expressed inthe central nervous (i.e. amygdala cerebellum, hippocampus) system andto a lesser amount in the periphery. CB2, which is encoded by the CNR2gene, is mostly expressed peripherally, on cells of the immune system,such as macrophages and T-cells (Ashton, J. C. et al. CurrNeuropharmacol 2007, 5(2), 73-80; Miller, A. M. et al. Br J Pharmacol2008, 153(2), 299-308; Centonze, D., et al. Curr Pharm Des 2008, 14(23),2370-42), and in the gastrointestinal system (Wright, K. L. et al. Br JPharmacol 2008, 153(2), 263-70). The CB2 receptor is also widelydistributed in the brain where it is found primarily on microglia andnot neurons (Cabral, G. A. et al. Br J Pharmacol 2008, 153(2): 240-51).

The interest in CB2 receptor agonists has been steadily on the riseduring the last decade (currently 30-40 patent applications/year) due tothe fact that several of the early compounds have been shown to havebeneficial effects in pre-clinical models for a number of human diseasesincluding chronic pain (Beltramo, M. Mini Rev Med Chem 2009, 9(1),11-25), atherosclerosis (Mach, F. et al. J Neuroendocrinol 2008, 20Suppl 1, 53-7), regulation of bone mass (Bab, I. et al. Br J Pharmacol2008, 153(2), 182-8), neuroinflammation (Cabral, G. A. et al. J LeukocBiol 2005, 78(6), 1192-7), ischemia/reperfusion injury (Pacher, P. etal. Br J Pharmacol 2008, 153(2), 252-62), systemic fibrosis(Akhmetshina, A. et al. Arthritis Rheum 2009, 60(4), 1129-36;Garcia-Gonzalez, E. et al. Rheumatology (Oxford) 2009, 48(9), 1050-6),liver fibrosis (Julien, B. et al. Gastroenterology 2005, 128(3), 742-55;Munoz-Luque, J. et al. J Pharmacol Exp Ther 2008, 324(2), 475-83).

Ischemia/reperfusion (I/R) injury is the principal cause of tissuedamage occurring in conditions such as stroke, myocardial infarction,cardiopulmonary bypass and other vascular surgeries, and organtransplantation, as well as a major mechanism of end-organ damagecomplicating the course of circulatory shock of various etiologies. Allthese conditions are characterized by a disruption of normal bloodsupply resulting in an insufficient tissue oxygenation. Re-oxygenatione.g., reperfusion is the ultimate treatment to restore normal tissueoxygenation. However the absence of oxygen and nutrients from bloodcreates a condition in which the restoration of circulation results infurther tissue damage. The damage of reperfusion injury is due in partto the inflammatory response of damaged tissues. White blood cells,carried to the area by the newly returning blood, release a host ofinflammatory factors such as interleukins as well as free radicals inresponse to tissue damage. The restored blood flow reintroduces oxygenwithin cells that damages cellular proteins, DNA, and the plasmamembrane.

Remote ischemic preconditioning (RIPC) represents a strategy forharnessing the body's endogenous protective capabilities against theinjury incurred by ischemia and reperfusion. It describes the intriguingphenomenon in which transient non-lethal ischemia and reperfusion of oneorgan or tissue confers resistance to a subsequent episode of “lethal”ischemia reperfusion injury in a remote organ or tissue. The actualmechanism through which transient ischemia and reperfusion of an organor tissue confers protection is currently unknown although severalhypotheses have been proposed.

The humoral hypothesis proposes that the endogenous substance (such asadenosine, bradykinin, opioids, CGRP, endocannabinoids, Angiotensin I orsome other as yet unidentified humoral factor) generated in the remoteorgan or tissue enters the blood stream and activates its respectivereceptor in the target tissue and thereby recruiting the variousintracellular pathways of cardioprotection implicated in ischemicpreconditioning.

Recent data indicates that endocannabinnoids and their receptors, inparticular CB2 might be involved in pre-conditioning and contribute toprevent reperfusion injury by downregulation of the inflammatoryresponse (Pacher, P. et al. Br J Pharmacol 2008, 153(2), 252-62).Specifically, recent studies using CB2 tool agonists demonstrated theefficacy of this concept for reducing the I/R injury in the heart(Defer, N. et al. Faseb J 2009, 23(7), 2120-30), the brain (Zhang, M. etal. J Cereb Blood Flow Metab 2007, 27(7), 1387-96), the liver (Batkai,S. et al. Faseb J 2007, 21(8), 1788-800) and the kidney (Feizi, A. etal. Exp Toxicol Pathol 2008, 60(4-5), 405-10).

Moreover, over the last few years, a growing body of literatureindicates that CB2 can also be of interest in sub-chronic and chronicsetting. Specific upregulation of CB1 and CB2 has been shown to beassociated in animal models of chronic diseases associated with fibrosis(Garcia-Gonzalez, E. et al. Rheumatology (Oxford) 2009, 48(9), 1050-6;Yang, Y. Y. et al. Liver Int 2009, 29(5), 678-85) with a relevantexpression of CB2 in myofibroblasts, the cells responsible for fibrosisprogression.

Activation of CB2 receptor by selective CB2 agonist has in fact beenshown to exert anti-fibrotic effect in diffuse systemic sclerosis(Garcia-Gonzalez, E. et al. Rheumatology (Oxford) 2009, 48(9), 1050-6)and CB2 receptor has emerged as a critical target in experimental dermalfibrosis (Akhmetshina, A. et al. Arthritis Rheum 2009, 60(4), 1129-36)and in liver pathophysiology, including fibrogenesis associated withchronic liver diseases (Lotersztajn, S. et al. Gastroenterol Clin Biol2007, 31(3), 255-8; Mallat, A. et al. Expert Opin Ther Targets 2007,11(3), 403-9; Lotersztajn, S. et al. Br J Pharmacol 2008, 153(2),286-9).

The compounds of the invention bind to and modulate the CB2 receptor andhave lower CB1 receptor activity.

In the present description the term “alkyl”, alone or in combination,signifies a straight-chain or branched-chain alkyl group with 1 to 8carbon atoms, particularly a straight or branched-chain alkyl group with1 to 6 carbon atoms and more particularly a straight or branched-chainalkyl group with 1 to 4 carbon atoms. Examples of straight-chain andbranched-chain C₁-C₈ alkyl groups are methyl, ethyl, propyl, isopropyl,butyl, isobutyl, tert.-butyl, the isomeric pentyls, the isomeric hexyls,the isomeric heptyls and the isomeric octyls, particularly methyl,ethyl, propyl, butyl and pentyl more particularly methyl, ethyl, propyl,isopropyl, isobutyl, tert.-butyl and isopentyl. Particular examples ofalkyl are methyl, ethyl, isopropyl and tert.-butyl, in particular methyland tert.-butyl.

The term “cycloalkyl”, alone or in combination, signifies a cycloalkylring with 3 to 8 carbon atoms and particularly a cycloalkyl ring with 3to 6 carbon atoms. Examples of cycloalkyl are cyclopropyl, cyclobutyl,cyclopentyl and cyclohexyl, cycloheptyl and cyclooctyl. Particularexamples of “cycloalkyl” are cyclopropyl and cyclobutyl. A particularexample of “cycloalkyl” is cyclopropyl.

The term “alkoxy”, alone or in combination, signifies a group of theformula alkyl-O— in which the term “alkyl” has the previously givensignificance, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy,isobutoxy, sec-butoxy and tert.-butoxy. Particular “alkoxy” are methoxyand tert.-butoxy, and in particular methoxy.

The term “oxy”, alone or in combination, signifies the —O— group.

The term “oxa”, alone or in combination, denotes an intracyclic —O—group.

The term “oxo”, alone or in combination, signifies the ═O group.

The terms “halogen” or “halo”, alone or in combination, signifiesfluorine, chlorine, bromine or iodine and particularly fluorine,chlorine or bromine, more particularly fluorine and chlorine. The term“halo”, in combination with another group, denotes the substitution ofsaid group with at least one halogen, particularly substituted with oneto five halogens, particularly one to four halogens, i.e. one, two,three or four halogens. A particular “halogen” is fluorine.

The term “haloalkyl”, alone or in combination, denotes an alkyl groupsubstituted with at least one halogen, particularly substituted with oneto five halogens, particularly one to three halogens. A particular“haloalkyl” is trifluoromethyl.

The term “haloalkoxy” or “haloalkyloxy”, alone or in combination,denotes an alkoxy group substituted with at least one halogen,particularly substituted with one to five halogens, particularly one tothree halogens. Particular “haloalkoxy” are pentafluoropropyloxy andtrifluoropropyloxy, fluoroethoxy, fluoropropyloxy, difluoroethyloxy anddifluoropropyloxy. Particular “haloalkoxy” are pentafluoropropyloxy andtrifluoropropyloxy.

The terms “hydroxyl” and “hydroxy”, alone or in combination, signify the—OH group.

The term “carbonyl”, alone or in combination, signifies the —C(O)—group.

The term “amino”, alone or in combination, signifies the primary aminogroup (—NH₂), the secondary amino group (—NH—), or the tertiary aminogroup (—N—).

The term “aminocarbonyl”, alone or in combination, signifies the—C(O)—NH₂ group.

The term “sulfonyl”, alone or in combination, signifies the —S(O)₂—group.

The term “pharmaceutically acceptable salts” refers to those salts whichretain the biological effectiveness and properties of the free bases orfree acids, which are not biologically or otherwise undesirable. Thesalts are formed with inorganic acids such as hydrochloric acid,hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid,particularly hydrochloric acid, and organic acids such as acetic acid,propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid,malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid,benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid,ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid,N-acetylcystein. In addition these salts may be prepared form additionof an inorganic base or an organic base to the free acid. Salts derivedfrom an inorganic base include, but are not limited to, the sodium,potassium, lithium, ammonium, calcium, magnesium salts. Salts derivedfrom organic bases include, but are not limited to salts of primary,secondary, and tertiary amines, substituted amines including naturallyoccurring substituted amines, cyclic amines and basic ion exchangeresins, such as isopropylamine, trimethylamine, diethylamine,triethylamine, tripropylamine, ethanolamine, lysine, arginine,N-ethylpiperidine, piperidine, polyamine resins. The compound of formula(I) can also be present in the form of zwitterions. Particularlypreferred pharmaceutically acceptable salts of compounds of formula (I)are the salts of hydrochloric acid, hydrobromic acid, sulfuric acid,phosphoric acid and methanesulfonic acid.

“Pharmaceutically acceptable esters” means that the compound of generalformula (I) may be derivatised at functional groups to providederivatives which are capable of conversion back to the parent compoundsin vivo. Examples of such compounds include physiologically acceptableand metabolically labile ester derivatives, such as methoxymethylesters, methylthiomethyl esters and pivaloyloxymethyl esters.Additionally, any physiologically acceptable equivalents of the compoundof general formula (I), similar to the metabolically labile esters,which are capable of producing the parent compound of general formula(I) in vivo, are within the scope of this invention.

If one of the starting materials or compounds of formula (I) contain oneor more functional groups which are not stable or are reactive under thereaction conditions of one or more reaction steps, appropriateprotecting groups (as described e.g. in “Protective Groups in OrganicChemistry” by T. W. Greene and P. G. M. Wuts, 3^(rd) Ed., 1999, Wiley,New York) can be introduced before the critical step applying methodswell known in the art. Such protecting groups can be removed at a laterstage of the synthesis using standard methods described in theliterature. Examples of protecting groups are tert-butoxycarbonyl (Boc),9-fluorenylmethyl carbamate (Fmoc), 2-trimethylsilylethyl carbamate(Teoc), carbobenzyloxy (Cbz) and p-methoxybenzyloxycarbonyl (Moz).

The compound of formula (I) can contain several asymmetric centers andcan be present in the form of optically pure enantiomers, mixtures ofenantiomers such as, for example, racemates, mixtures ofdiastereoisomers, diastereoisomeric racemates or mixtures ofdiastereoisomeric racemates.

The term “asymmetric carbon atom” means a carbon atom with fourdifferent substituents. According to the Cahn-Ingold-Prelog Conventionan asymmetric carbon atom can be of the “R” or “S” configuration.

The invention relates in particular to a compound of formula (I) wherein

-   -   R² is alkyl, pyrrolidinyl, cycloalkyl, haloazetidinyl,        haloalkyl, cycloalkylalkoxy or haloalkyloxy;    -   one of R³ and R⁴ is alkyl, cycloalkyl, haloalkyl or hydroxyalkyl        and the other one is alkyl, alkyloxyalkyl,        (haloazetidinyl)(cycloalkyloxy)pyridinylcarbonyloxyalkyl,        haloalkylcycloalkyl, hydroxyalkyl, phenylalkyl,        alkoxycarbonylalkyl, carboxyalkyl, alkylaminocarbonylalkyl,        (alkyloxadiazolyl)(cycloalkylalkyl)alkyl,        (alkyloxadiazolyl)(cycloalkyl)alkyl, pyridazinylalkyl,        aminocarbonylalkyl, alkyloxadiazolylalkyl, alkyltetrazolylalkyl,        formyl, phenyl, dialkylpyrazolyl, alkylcarbonylpiperidinyl or        cycloalkylalkyl;    -   or R³ and R⁴ together with the nitrogen atom to which they are        attached form heterocyclyl or substituted heterocyclyl;    -   wherein heterocyclyl is 6-oxa-1-aza-spiro[3.3]heptyl,        oxazolidinyl, morpholinyl, pyrrolidinyl, piperazinyl,        2-oxa-5-aza-spiro[3.4]octyl, piperidinyl,        6-aza-bicyclo[3.2.1.]octyl, imidazolidinyl,        4-aza-spiro[2.4]heptyl, 2-aza-bicyclo[2.2.1]heptyl,        2-thia-5-aza-bicyclo[2.2.1]heptyl,        2,5-diazabicyclo[2.2.1]heptyl, 2-oxa-5-aza-bicyclo[2.2.1]heptyl,        hexahydrofuro[2,3-c]pyrrolyl, 2-thia-6-aza-spiro[3.3]heptyl,        1,8-diaza-spiro[4.5]decyl, 1-oxa-7-aza-spiro[4.4]nonyl,        5-oxa-2-aza-spiro[3.4]octyl, 8-oxa-3-aza-bicyclo[3.2.1]octyl,        3-oxa-8-aza-bicyclo[3.2.1]octyl, thiomorpholinyl, thiazolidinyl,        5-aza-spiro[3.4]octyl, azetidinyl, 5-aza-spiro[2.4]heptyl or        3-aza-bicyclo[3.1.0]hexyl; and    -   wherein substituted heterocyclyl is heterocyclyl substituted        with one to four substituents independently selected from alkyl,        oxo, hydroxyl, carboxyl, alkylcarbonylamino, alkyloxyalkyl,        hydroxyalkyl, aminocarbonyl, halogen, phenylalkyl, phenyl,        alkoxycarbonyl, cycloalkylalkyl and phenylalkoxycarbonyl.

The invention further relates in particular to:

A compound of formula (I) wherein R¹ is cycloalkylalkoxy,tetrahydrofuranylalkoxy, alkylsulfonyl or halophenylalkyl;

A compound of formula (I) wherein R¹ is cyclopropylmethoxy,tetrahydrofuranylmethoxy, isobutylsulfonyl or fluorophenylmethyl;

A compound of formula (I) wherein R² is haloazetidinyl, cycloalkyl orhalocycloalkyl;

A compound of formula (I) wherein R² is difluoroazetidinyl, cyclopropylor fluorocyclobutyl;

A compound of formula (I) wherein R² is haloazetidinyl or cycloalkyl;

A compound of formula (I) wherein R² is difluoroazetidinyl orcyclopropyl;

A compound of formula (I) wherein one of R³ and R⁴ is alkyl and theother one is alkyl or haloalkylcycloalkyl;

A compound of formula (I) wherein one of R³ and R⁴ is methyl and theother one is tert.-butyl or trifluoromethylcyclopropyl;

A compound of formula (I) wherein R³ and R⁴ together with the nitrogenatom to which they are attached form heterocyclyl or substitutedheterocyclyl, wherein heterocyclyl is oxazolidinyl, morpholinyl,pyrrolidinyl, 6-aza-bicyclo[3.2.1.]octyl, 4-aza-spiro[2.4]heptyl,2-thia-5-aza-bicyclo[2.2.1]heptyl, 5-aza-spiro[3.4]octyl,5-aza-spiro[2.4]heptyl, 1,8-diaza-spiro[4.5]decyl, thiazolidinyl or5-aza-spiro[2.4]heptyl, and wherein substituted heterocyclyl isheterocyclyl substituted with one to three substituents independentlyselected from alkyl, hydroxyalkyl, halogen, aminocarbonyl,alkoxycarbonyl, oxo or hydroxyl;

A compound of formula (I) wherein R³ and R⁴ together with the nitrogenatom to which they are attached form heterocyclyl or substitutedheterocyclyl, wherein heterocyclyl is oxazolidinyl, morpholinyl,pyrrolidinyl, 6-aza-bicyclo[3.2.1.]octyl, 4-aza-spiro[2.4]heptyl,2-thia-5-aza-bicyclo[2.2.1]heptyl, 5-aza-spiro[3.4]octyl,5-aza-spiro[2.4]heptyl, 1,8-diaza-spiro[4.5]decyl, thiazolidinyl or5-aza-spiro[2.4]heptyl, and wherein substituted heterocyclyl isheterocyclyl substituted with one to three substituents independentlyselected from methyl, hydroxymethyl, fluoro, aminocarbonyl,tert.-butoxycarbonyl, oxo or hydroxyl;

A compound of formula (I) wherein R³ and R⁴ together with the nitrogenatom to which they are attached form dimethyloxazolidinyl,dimethylmorpholinyl, dimethylpyrrolidinyl,trimethyl-6-aza-bicyclo[3.2.1.]octyl,(hydroxymethyl)(difluoro)pyrrolidinyl, 4-aza-spiro[2.4]heptyl,(aminocarbonyl)(difluoro)pyrrolidinyl,2-thia-5-aza-bicyclo[2.2.1]heptyl,(aminocarbonyl)(dimethyl)pyrrolidinyl, 5-aza-spiro[3.4]octyl,difluoro-5-aza-spiro[2.4]heptyl, 5-aza-spiro[2.4]heptyl,tert.-butoxycarbonyl-1,8-diaza-spiro[4.5]decyl,aminocarbonyl-1,1-dioxo-1λ6-thiazolidinyl,aminocarbonyl-1,1-dioxo-1,3-thiazolidinyl,(aminocarbonyl)(methyl)(hydroxyl)pyrrolidinyl or(aminocarbonyl)-5-aza-spiro[2.4]heptyl;

A compound of formula (I) wherein R³ and R⁴ together with the nitrogenatom to which they are attached form heterocyclyl or substitutedheterocyclyl, wherein heterocyclyl is oxazolidinyl, morpholinyl,pyrrolidinyl, 6-aza-bicyclo[3.2.1.]octyl, 4-aza-spiro[2.4]heptyl,2-thia-5-aza-bicyclo[2.2.1]heptyl, 5-aza-spiro[3.4]octyl,5-aza-spiro[2.4]heptyl, 1,8-diaza-spiro[4.5]decyl or thiazolidinyl, andwherein substituted heterocyclyl is heterocyclyl substituted with one tothree substituents independently selected from alkyl, hydroxyalkyl,halogen, aminocarbonyl, alkoxycarbonyl and oxo;

A compound of formula (I) wherein R³ and R⁴ together with the nitrogenatom to which they are attached form heterocyclyl or substitutedheterocyclyl, wherein heterocyclyl is oxazolidinyl, morpholinyl,pyrrolidinyl, 6-aza-bicyclo[3.2.1.]octyl, 4-aza-spiro[2.4]heptyl,2-thia-5-aza-bicyclo[2.2.1]heptyl, 5-aza-spiro[3.4]octyl,5-aza-spiro[2.4]heptyl, 1,8-diaza-spiro[4.5]decyl or thiazolidinyl, andwherein substituted heterocyclyl is heterocyclyl substituted with one tothree substituents independently selected from methyl, hydroxymethyl,fluoro, aminocarbonyl, tert.-butoxycarbonyl and oxo;

A compound of formula (I) wherein R³ and R⁴ together with the nitrogenatom to which they are attached form dimethyloxazolidinyl,dimethylmorpholinyl, dimethylpyrrolidinyl,trimethyl-6-aza-bicyclo[3.2.1.]octyl,(hydroxymethyl)(difluoro)pyrrolidinyl, 4-aza-spiro[2.4]heptyl,(aminocarbonyl)(difluoro)pyrrolidinyl,2-thia-5-aza-bicyclo[2.2.1]heptyl,(aminocarbonyl)(dimethyl)pyrrolidinyl, 5-aza-spiro[3.4]octyl,difluoro-5-aza-spiro[2.4]heptyl, 5-aza-spiro[2.4]heptyl,tert.-butoxycarbonyl-1,8-diaza-spiro[4.5]decyl oraminocarbonyl-1,1-dioxo-1λ⁶-thiazolidinyl;

A compound of formula (I) wherein R³ and R⁴ together with the nitrogenatom to which they are attached form 6-oxa-1-aza-spiro[3.3]heptyl,dialkyloxazolidinyl, dialkylmorpholinyl, dialkylpyrrolidinyl,(dialkyl)(oxo)piperazinyl, (hydroxyl)(alkyl)pyrrolidinyl,2-oxa-5-aza-spiro[3.4]octyl, alkylcarbonylaminopyrrolidinyl,dialkylpiperidinyl, trialkyl-6-aza-bicyclo[3.2.1.]octyl,alkyloxyalkylpyrrolidinyl, (halo)(hydroxyalkyl)pyrrolidinyl,(dialkyl)(oxo)imidazolyl, 4-aza-spiro[2.4]heptyl,(dialkyl)(oxo)pyrrolidinyl-piperidinyl, 2-aza-bicyclo[2.2.1]heptyl,(aminocarbonyl)(halo)pyrrolidinyl, (hydroxyl)(alkyl)piperidinyl,2-thia-5-aza-bicyclo[2.2.1]heptyl,phenylalkyl-2,5-diazabicyclo[2.2.1]heptyl, (phenyl)(alkyl)piperidinyl,2-oxa-5-aza-bicyclo[2.2.1]heptyl, (hydroxyl)(dialkyl)piperidinyl,(alkoxycarbonyl)(phenyl)piperidinyl, hexahydrofuro[2,3-c]pyrrolyl,2,2-dioxo-2λ⁶-thia-6-aza-spiro[3.3]heptyl,(alkoxycarbonyl)-1,8-diaza-spiro[4.5]decyl,(aminocarbonyl)(dialkyl)pyrrolidinyl,(aminocarbonyl)(hydroxyl)pyrrolidinyl,hydroxy-1-oxa-7-aza-spiro[4.4]nonyl,hydroxy-5-oxa-2-aza-spiro[3.4]octyl, 8-oxa-3-aza-bicyclo[3.2.1]octyl,3-oxa-8-aza-bicyclo[3.2.1]octyl, aminocarbonylpiperidinyl,aminocarbonylthiomorpholinyl, aminocarbonylthiazolidinyl,5-oxa-2-aza-spiro[3.4]octyl, 1-oxa-7-aza-spiro[4.4]nonyl,5-aza-spiro[3.4]octyl, haloazetidinyl, halo-5-aza-spiro[2.4]heptyl,5-aza-spiro[2.4]heptyl, cycloalkylalkylpiperazinyl,alkoxycarbonyl-3-aza-bicyclo[3.1.0]hexyl,phenylalkoxycarbonylpiperazinyl, carboxy-3-aza-bicyclo[3.1.0]hexyl,1,8-diaza-spiro[4.5]decyl, aminocarbonylpyrrolidinyl,aminocarbonyl-1,1-dioxo-1λ⁶-thiazolidinyl,aminocarbonyl-1-oxo-1λ⁴-thiazolidinyl, tetrafluoropyrrolidinyl,(dialkyl)(aminocarbonyl)thiazolidinyl,(aminocarbonyl)(halo)pyrrolidinyl,(aminocarbonyl)-1-oxo-1,3-thiazolidinyl,(aminocarbonyl)-1,1-dioxo-1,3-thiazolidinyl,(aminocarbonyl)(hydroxyl)(alkyl)pyrrolidinyl,(aminocarbonyl)-5-aza-spiro[2.4]heptyl, (hydroxyhaloalkyl)pyrrolidinyl,(haloalkyl)(hydroxyalkyl)pyrrolidinyl,(haloalkyl)(hydroxyl)pyrrolidinyl, (haloalkyl)(hydroxyl)azetidinyl,1,3,3a,4,6,6a-hexahydrofuro[3,4-c]pyrrolyl,(halo)(hydroxyalkyl)azetidinyl or (halo)(alkyl)azetidinyl; and

A compound of formula (I) wherein R³ and R⁴ together with the nitrogenatom to which they are attached form 6-oxa-1-aza-spiro[3.3]heptyl,dialkyloxazolidinyl, dialkylmorpholinyl, dialkylpyrrolidinyl,(dialkyl)(oxo)piperazinyl, (hydroxyl)(alkyl)pyrrolidinyl,2-oxa-5-aza-spiro[3.4]octyl, alkylcarbonylaminopyrrolidinyl,dialkylpiperidinyl, trialkyl-6-aza-bicyclo[3.2.1.]octyl,alkyloxyalkylpyrrolidinyl, (halo)(hydroxyalkyl)pyrrolidinyl,(dialkyl)(oxo)imidazolyl, 4-aza-spiro[2.4]heptyl,(dialkyl)(oxo)pyrrolidinyl-piperidinyl, 2-aza-bicyclo[2.2.1]heptyl,(aminocarbonyl)(halo)pyrrolidinyl, (hydroxyl)(alkyl)piperidinyl,2-thia-5-aza-bicyclo[2.2.1]heptyl,phenylalkyl-2,5-diazabicyclo[2.2.1]heptyl, (phenyl)(alkyl)piperidinyl,2-oxa-5-aza-bicyclo[2.2.1]heptyl, (hydroxyl)(dialkyl)piperidinyl,(alkoxycarbonyl)(phenyl)piperidinyl, hexahydrofuro[2,3-c]pyrrolyl,2,2-dioxo-2λ⁶-thia-6-aza-spiro[3.3]heptyl,(alkoxycarbonyl)-1,8-diaza-spiro[4.5]decyl,(aminocarbonyl)(dialkyl)pyrrolidinyl,(aminocarbonyl)(hydroxyl)pyrrolidinyl,hydroxy-1-oxa-7-aza-spiro[4.4]nonyl,hydroxy-5-oxa-2-aza-spiro[3.4]octyl, 8-oxa-3-aza-bicyclo[3.2.1]octyl,3-oxa-8-aza-bicyclo[3.2.1]octyl, aminocarbonylpiperidinyl,aminocarbonylthiomorpholinyl, aminocarbonylthiazolidinyl,5-oxa-2-aza-spiro[3.4]octyl, 1-oxa-7-aza-spiro[4.4]nonyl,5-aza-spiro[3.4]octyl, haloazetidinyl, halo-5-aza-spiro[2.4]heptyl,5-aza-spiro[2.4]heptyl, cycloalkylalkylpiperazinyl,alkoxycarbonyl-3-aza-bicyclo[3.1.0]hexyl,phenylalkoxycarbonylpiperazinyl, carboxy-3-aza-bicyclo[3.1.0]hexyl,1,8-diaza-spiro[4.5]decyl, aminocarbonylpyrrolidinyl,aminocarbonyl-1,1-dioxo-1λ⁶-thiazolidinyl,aminocarbonyl-1-oxo-1λ⁴-thiazolidinyl, tetrafluoropyrrolidinyl or(dialkyl)(aminocarbonyl)thiazolidinyl.

The invention further relates to a compound selected from:

-   6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic    acid tert-butyl-methyl-amide;-   6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic    acid dimethylamide;-   5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid    tert-butyl-methyl-amide;-   5-Cyclopropyl-6-(tetrahydro-furan-2-ylmethoxy)-pyridine-2-carboxylic    acid tert-butyl-methyl-amide;-   5-Cyclopropyl-6-(4-fluoro-benzyl)-pyridine-2-carboxylic acid    tert-butyl-methyl-amide;-   5-Cyclopropyl-6-(2-methyl-propane-1-sulfonyl)-pyridine-2-carboxylic    acid tert-butyl-methyl-amide;-   6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic    acid tert-butyl-ethyl-amide;-   6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic    acid diisopropylamide;-   6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic    acid (2-methoxy-1,1-dimethyl-ethyl)-methyl-amide;-   [6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridin-2-yl]-(6-oxa-1-aza-spiro[3.3]hept-1-yl)-methanone;-   [6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridin-2-yl]-(2-oxa-6-aza-spiro[3.3]hept-6-yl)-methanone;-   6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic    acid    2-{[6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carbonyl]-methyl-amino}-2-methyl-propyl    ester;-   5-Cyclopropyl-6-(2,2,2-trifluoro-1-methyl-ethoxy)-pyridine-2-carboxylic    acid tert-butyl-methyl-amide;-   [6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridin-2-yl]-(4,4-dimethyl-oxazolidin-3-yl)-methanone;-   6-(Tetrahydro-furan-2-ylmethoxy)-5-trifluoromethyl-pyridine-2-carboxylic    acid tert-butyl-methyl-amide;-   6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic    acid methyl-(1-trifluoromethyl-cyclopropyl)-amide;-   [6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridin-2-yl]-(3,3-dimethyl-morpholin-4-yl)-methanone;-   [6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridin-2-yl]-(2,2-dimethyl-pyrrolidin-1-yl)-methanone;-   6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic    acid (2-hydroxy-1,1-dimethyl-ethyl)-(2-methoxy-ethyl)-amide;-   6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic    acid tert-butyl-(2-methoxy-ethyl)-amide;-   6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic    acid ethyl-(1-trifluoromethyl-cyclopropyl)-amide;-   6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic    acid benzyl-(1-trifluoromethyl-cyclopropyl)-amide;-   {tert-Butyl-[6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carbonyl]-amino}-acetic    acid ethyl ester;-   {tert-Butyl-[6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carbonyl]-amino}-acetic    acid;-   6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic    acid benzyl-tert-butyl-amide;-   6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic    acid tert-butyl-methylcarbamoylmethyl-amide;-   6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic    acid tert-butyl-dimethylcarbamoylmethyl-amide;-   4-[6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carbonyl]-3,3-dimethyl-piperazin-2-one;-   4-[6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carbonyl]-3,3-diethyl-piperazin-2-one;-   [5-Cyclopropyl-6-(2-methyl-propane-1-sulfonyl)-pyridin-2-yl]-(2,2-dimethyl-pyrrolidin-1-yl)-methanone;-   [5-Cyclopropyl-6-(2-methyl-propane-1-sulfonyl)-pyridin-2-yl]-(4,4-dimethyl-oxazolidin-3-yl)-methanone;-   6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic    acid    [(S)-2-cyclopropyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethyl]-methyl-amide;-   5-Cyclopropyl-6-(tetrahydro-pyran-4-ylmethoxy)-pyridine-2-carboxylic    acid    [cyclopropyl-(5-methyl-[1,2,4]oxadiazol-3-yl)-methyl]-methyl-amide;-   (+)-6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic    acid methyl-(3-methyl-1-pyridazin-3-yl-butyl)-amide;-   6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic    acid tert-butyl-carbamoylmethyl-amide;-   6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic    acid tert-butyl-(5-methyl-[1,3,4]oxadiazol-2-ylmethyl)-amide;-   [6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridin-2-yl]-(3-hydroxy-3-methyl-pyrrolidin-1-yl)-methanone;-   [6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridin-2-yl]-(2-oxa-5-aza-spiro[3.4]oct-5-yl)-methanone;-   6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic    acid ethyl-(2-methoxy-ethyl)-amide;-   6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic    acid tert-butyl-(1-methyl-1H-tetrazol-5-ylmethyl)-amide;-   N-{1-[6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carbonyl]-pyrrolidin-3-yl}-acetamide;-   [5-Cyclopropyl-6-(4-fluoro-benzyl)-pyridin-2-yl]-(4,4-dimethyl-piperidin-1-yl)-methanone;-   [5-Cyclopropyl-6-(tetrahydro-furan-2-ylmethoxy)-pyridin-2-yl]-(4,4-dimethyl-piperidin-1-yl)-methanone;-   [5-Cyclopropyl-6-(4-fluoro-benzyl)-pyridin-2-yl]-(4,4-dimethyl-oxazolidin-3-yl)-methanone;-   [6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridin-2-yl]-((1S,5R)-1,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct-6-yl)-methanone;-   [6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridin-2-yl]-((R)-2-methoxymethyl-pyrrolidin-1-yl)-methanone;-   (6-Chloro-5-cyclopropylmethoxy-pyridin-2-yl)-(2,2-dimethyl-pyrrolidin-1-yl)-methanone;-   (6-Cyclopropylmethoxy-5-trifluoromethoxy-pyridin-2-yl)-(4,4-dimethyl-oxazolidin-3-yl)-methanone;-   (6-Chloro-5-cyclopropylmethoxy-pyridin-2-yl)-(4,4-dimethyl-oxazolidin-3-yl)-methanone;-   6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic    acid (1-acetyl-piperidin-4-yl)-cyclopropyl-amide;-   6-(Cyclopropylmethoxy)-5-(3,3-difluoroazetidin-1-yl)-N-formyl-N-methylpyridine-2-carboxamide;-   6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic    acid methyl-phenyl-amide;-   [6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridin-2-yl]-((S)-4,4-difluoro-2-hydroxymethyl-pyrrolidin-1-yl)-methanone;-   6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic    acid (1,4-dimethyl-1H-pyrazol-3-yl)-methyl-amide;-   [6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridin-2-yl]-(2,2-dimethyl-morpholin-4-yl)-methanone;-   (R)-2-tert-Butyl-1-[6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carbonyl]-3-methyl-imidazolidin-4-one;-   (4-Aza-spiro[2.4]hept-4-yl)-[6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridin-2-yl]-methanone;-   3-{1-[6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carbonyl]-piperidin-4-yl}-5,5-dimethyl-pyrrolidin-2-one;-   (1S,4R)-2-Aza-bicyclo[2.2.1]hept-2-yl-[6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridin-2-yl]-methanone;-   (S)-1-[6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carbonyl]-4,4-difluoro-pyrrolidine-2-carboxylic    acid amide;-   [6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridin-2-yl]-(4-hydroxy-4-methyl-piperidin-1-yl)-methanone;-   [6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridin-2-yl]-(1S,4S)-2-thia-5-aza-bicyclo[2.2.1]hept-5-yl-methanone;-   ((1S,4S)-5-Benzyl-2,5-diaza-bicyclo[2.2.1]hept-2-yl)-[6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridin-2-yl]-methanone;-   [6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridin-2-yl]-(2-methyl-3-phenyl-piperidin-1-yl)-methanone;-   [6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridin-2-yl]-(1S,4S)-2-oxa-5-aza-bicyclo[2.2.1]hept-5-yl-methanone;-   [6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridin-2-yl]-(4-hydroxy-2,2-dimethyl-piperidin-1-yl)-methanone;-   1-[6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carbonyl]-2-phenylpiperidine-3-carboxylic    acid ethyl ester;-   (S)-1-(5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carbonyl)-4,4-difluoro-pyrrolidine-2-carboxylic    acid amide;-   (2S,4S)-1-(5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carbonyl)-4-fluoro-pyrrolidine-2-carboxylic    acid amide;-   [6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridin-2-yl]-(hexahydrofuro[2,3-c]pyrrol-5-yl)-methanone;-   [6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridin-2-yl]-(2,2-dioxo-2λ6-thia-6-aza-spiro[3.3]hept-6-yl)-methanone;-   6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic    acid tert-butyl-(2-carbamoyl-ethyl)-amide;-   (S)-1-(5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carbonyl)-pyrrolidine-2-carboxylic    acid amide;-   1-[6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carbonyl]-1,8-diaza-spiro[4.5]decane-8-carboxylic    acid tert-butyl ester;-   (S)-1-{5-Cyclopropyl-6-[(R,S)-1-(tetrahydro-furan-2-yl)methoxy]-pyridine-2-carbonyl}-4,4-difluoro-pyrrolidine-2-carboxylic    acid amide;-   (S)-1-[5-Cyclopropyl-6-(4-fluoro-benzyl)-pyridine-2-carbonyl]-4,4-difluoro-pyrrolidine-2-carboxylic    acid amide;-   (+)-1-[6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carbonyl]-4,4-dimethyl-pyrrolidine-2-carboxylic    acid amide;-   (−)-1-[6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carbonyl]-4,4-dimethyl-pyrrolidine-2-carboxylic    acid amide;-   (2S,4S)-1-[6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carbonyl]-4-hydroxy-pyrrolidine-2-carboxylic    acid amide;-   (2S,4S)-1-[6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carbonyl]-4-fluoro-pyrrolidine-2-carboxylic    acid amide;-   6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic    acid cyclopropyl-(5-methyl-[1,3,4]oxadiazol-2-ylmethyl)-amide;-   [6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridin-2-yl]-(3-hydroxy-1-oxa-7-aza-spiro[4.4]non-7-yl)-methanone;-   [6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridin-2-yl]-(7-hydroxy-5-oxa-2-aza-spiro[3.4]oct-2-yl)-methanone;-   [5-Cyclopropyl-6-(2,2,3,3,3-pentafluoro-propoxy)-pyridin-2-yl]-(2,2-dimethyl-pyrrolidin-1-yl)-methanone;-   [6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridin-2-yl]-(1S,5R)-8-oxa-3-aza-bicyclo[3.2.1]oct-3-yl-methanone;-   [6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridin-2-yl]-(1R,5S)-3-oxa-8-aza-bicyclo[3.2.1]oct-8-yl-methanone;-   (R)-1-[5-Cyclopropyl-6-(2,2,3,3,3-pentafluoro-propoxy)-pyridine-2-carbonyl]-4,4-difluoro-pyrrolidine-2-carboxylic    acid amide;-   1-(5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carbonyl)-piperidine-2-carboxylic    acid amide;-   4-(5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carbonyl)-thiomorpholine-3-carboxylic    acid amide;-   1-(5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carbonyl)-4,4-dimethyl-pyrrolidine-2-carboxylic    acid amide;-   (+)-1-(5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carbonyl)-piperidine-2-carboxylic    acid amide;-   (−)-1-(5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carbonyl)-piperidine-2-carboxylic    acid amide;-   (−)-4-(5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carbonyl)-thiomorpholine-3-carboxylic    acid amide;-   (+)-1-(5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carbonyl)-4,4-dimethyl-pyrrolidine-2-carboxylic    acid amide;-   (−)-1-(5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carbonyl)-4,4-dimethyl-pyrrolidine-2-carboxylic    acid amide;-   3-(5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carbonyl)-thiazolidine-4-carboxylic    acid amide;-   (−)-3-(5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carbonyl)-thiazolidine-4-carboxylic    acid amide;-   1-[6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carbonyl]-4,4-dimethyl-pyrrolidine-2-carboxylic    acid amide;-   [6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridin-2-yl]-(5-oxa-2-aza-spiro[3.4]oct-2-yl)-methanone;-   [6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridin-2-yl]-(1-oxa-7-aza-spiro[4.4]non-7-yl)-methanone;-   (5-Aza-spiro[3.4]oct-5-yl)-[6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridin-2-yl]-methanone;-   [6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridin-2-yl]-(3,3-difluoro-azetidin-1-yl)-methanone;-   [6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridin-2-yl]-(1,1-difluoro-5-aza-spiro[2.4]hept-5-yl)-methanone;-   (5-Aza-spiro[2.4]hept-5-yl)-[6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridin-2-yl]-methanone;-   6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic    acid cyclopropylmethyl-methyl-amide;-   [6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridin-2-yl]-(4-cyclopropylmethyl-piperazin-1-yl)-methanone;-   3-[6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carbonyl]-3-aza-bicyclo[3.1.0]hexane-6-carboxylic    acid ethyl ester;-   1-[6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carbonyl]-pyrrolidine-2-carboxylic    acid methyl ester;-   4-[6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carbonyl]-piperazine-1-carboxylic    acid benzyl ester;-   3-[6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carbonyl]-3-aza-bicyclo[3.1.0]hexane-6-carboxylic    acid;-   1-[5-Cyclopropyl-6-(4-fluoro-benzyl)-pyridine-2-carbonyl]-1,8-diaza-spiro[4.5]decane-8-carboxylic    acid tert-butyl ester;-   (−)-3-[6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carbonyl]-thiazolidine-4-carboxylic    acid amide;-   [5-Cyclopropyl-6-(4-fluoro-benzyl)-pyridin-2-yl]-(1,8-diaza-spiro[4.5]dec-1-yl)-methanone;-   1-[6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carbonyl]-pyrrolidine-2-carboxylic    acid amide;-   (−)-3-(5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carbonyl)-1,1-dioxo-1λ6-thiazolidine-4-carboxylic    acid amide;-   (1S,4R)-3-(5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carbonyl)-1-oxo-1λ4-thiazolidine-4-carboxylic    acid amide;-   (1R,4S)-3-(5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carbonyl)-1-oxo-1λ4-thiazolidine-4-carboxylic    acid amide;-   (+)-3-(5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carbonyl)-1,1-dioxo-1λ6-thiazolidine-4-carboxylic    acid amide;-   [6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridin-2-yl]-(3,3,4,4-tetrafluoro-pyrrolidin-1-yl)-methanone;-   [6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridin-2-yl]-(2,6-dimethyl-morpholin-4-yl)-methanone;-   (R)-3-[6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carbonyl]-5,5-dimethyl-thiazolidine-4-carboxylic    acid amide;-   (S)-1-[6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carbonyl]-5,5-dimethyl-pyrrolidine-2-carboxylic    acid amide; and-   3-[6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carbonyl]-thiazolidine-4-carboxylic    acid amide.

The invention further relates in particular to a compound selected from:

-   (2S,4R)-1-[5-Cyclopropyl-6-(cyclopropylmethoxy)pyridine-2-carbonyl]-4-fluoropyrrolidine-2-carboxamide;-   3-[6-(Cyclopropylmethoxy)-5-(3,3-difluoroazetidin-1-yl)pyridine-2-carbonyl]-1-oxo-1,3-thiazolidine-4-carboxamide;-   3-[6-(Cyclopropylmethoxy)-5-(3,3-difluoroazetidin-1-yl)pyridine-2-carbonyl]-1,1-dioxo-1,3-thiazolidine-4-carboxamide;-   (2S,4R)-1-[6-(Cyclopropylmethoxy)-5-(3,3-difluoroazetidin-1-yl)pyridine-2-carbonyl]-4-fluoropyrrolidine-2-carboxamide;-   (−)-3-[6-(Cyclopropylmethoxy)-5-(3,3-difluoroazetidin-1-yl)pyridine-2-carbonyl]-1,1-dioxo-1,3-thiazolidine-4-carboxamide;-   3-[6-(Cyclopropylmethoxy)-5-(3-methoxyazetidin-1-yl)pyridine-2-carbonyl]-1,1-dioxo-1,3-thiazolidine-4-carboxamide;-   (2S)-1-[6-(Cyclopropylmethoxy)-5-(1-hydroxycyclobutyl)pyridine-2-carbonyl]-4,4-difluoropyrrolidine-2-carboxamide;-   (2S)-1-[6-(Cyclopropylmethoxy)-5-(1-fluorocyclobutyl)pyridine-2-carbonyl]-4,4-difluoropyrrolidine-2-carboxamide;-   3-[6-(Cyclopropylmethoxy)-5-(1-hydroxycyclobutyl)pyridine-2-carbonyl]-1,1-dioxo-1,3-thiazolidine-4-carboxamide;-   (2S)-1-[6-(Cyclopropylmethoxy)-5-(3,3-difluoroazetidin-1-yl)pyridine-2-carbonyl]-4-hydroxy-4-methylpyrrolidine-2-carboxamide;-   3-[6-(Cyclopropylmethoxy)-5-(1-fluorocyclobutyl)pyridine-2-carbonyl]-1,1-dioxo-1,3-thiazolidine-4-carboxamide;-   (2S)-1-[6-(Cyclopropylmethoxy)-5-(3-fluorooxetan-3-yl)pyridine-2-carbonyl]-4,4-difluoropyrrolidine-2-carboxamide;-   5-[6-(Cyclopropylmethoxy)-5-(3,3-difluoroazetidin-1-yl)pyridine-2-carbonyl]-5-azaspiro[2.4]heptane-6-carboxamide;-   [6-(Cyclopropylmethoxy)-5-(3,3-difluoroazetidin-1-yl)pyridin-2-yl]-[3-(2,2,2-trifluoro-1-hydroxyethyl)pyrrolidin-1-yl]methanone;-   [6-(Cyclopropylmethoxy)-5-(3,3-difluoroazetidin-1-yl)pyridin-2-yl]-[3-(hydroxymethyl)-3-(trifluoromethyl)pyrrolidin-1-yl]methanone;-   [6-(Cyclopropylmethoxy)-5-(3,3-difluoroazetidin-1-yl)pyridin-2-yl]-[3-hydroxy-3-(trifluoromethyl)pyrrolidin-1-yl]methanone;-   [6-(Cyclopropylmethoxy)-5-(3,3-difluoroazetidin-1-yl)pyridin-2-yl]-[3-hydroxy-3-(trifluoromethyl)azetidin-1-yl]methanone;-   (+)-(2S)-1-[6-(Cyclopropylmethoxy)-5-(3,3-difluoroazetidin-1-yl)pyridine-2-carbonyl]-4-hydroxy-4-methylpyrrolidine-2-carboxamide;-   [5-Cyclopropyl-6-(cyclopropylmethoxy)pyridin-2-yl]-[3-(2,2,2-trifluoro-1-hydroxyethyl)pyrrolidin-1-yl]methanone;-   [5-Cyclopropyl-6-(cyclopropylmethoxy)pyridin-2-yl]-[3-(hydroxymethyl)-3-(trifluoromethyl)pyrrolidin-1-yl]methanone;-   [5-Cyclopropyl-6-(cyclopropylmethoxy)pyridin-2-yl]-[3-hydroxy-3-(trifluoromethyl)pyrrolidin-1-yl]methanone;-   [5-Cyclopropyl-6-(cyclopropylmethoxy)pyridin-2-yl]-[3-hydroxy-3-(trifluoromethyl)azetidin-1-yl]methanone;-   (6S)-5-[6-(Cyclopropylmethoxy)-5-(3,3-difluoroazetidin-1-yl)pyridine-2-carbonyl]-5-azaspiro[2.4]heptane-6-carboxamide;-   [(3aR,6aS)-1,3,3a,4,6,6a-Hexahydrofuro[3,4-c]pyrrol-5-yl]-[6-(cyclopropylmethoxy)-5-(3,3-difluoroazetidin-1-yl)pyridin-2-yl]methanone;-   (2S)-1-[5-(3,3-Difluoroazetidin-1-yl)-6-(2-fluoroethoxy)pyridine-2-carbonyl]-4,4-difluoro-pyrrolidine-2-carboxamide;-   [6-(Cyclopropylmethoxy)-5-(3,3-difluoroazetidin-1-yl)-2-pyridyl]-[3-fluoro-3-(hydroxymethyl)azetidin-1-yl]methanone;-   [6-(Cyclopropylmethoxy)-5-(3,3-difluoroazetidin-1-yl)-2-pyridyl]-(3-fluoro-3-methyl-azetidin-1-yl)methanone;-   (3-Cyclopropyl-3-fluoroazetidin-1-yl)-[6-(cyclopropylmethoxy)-5-(3,3-difluoroazetidin-1-yl)pyridin-2-yl]methanone;-   (−)-5-[6-(Cyclopropylmethoxy)-5-(3,3-difluoroazetidin-1-yl)pyridine-2-carbonyl]-5-azaspiro[2.4]heptane-4-carboxamide;    and-   (+)-5-[6-(Cyclopropylmethoxy)-5-(3,3-difluoroazetidin-1-yl)pyridine-2-carbonyl]-5-azaspiro[2.4]heptane-4-carboxamide.

The invention also relates in particular to a compound selected from:

-   6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic    acid tert-butyl-methyl-amide;-   5-Cyclopropyl-6-(tetrahydro-furan-2-ylmethoxy)-pyridine-2-carboxylic    acid tert-butyl-methyl-amide;-   [6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridin-2-yl]-(4,4-dimethyl-oxazolidin-3-yl)-methanone;-   6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic    acid methyl-(1-trifluoromethyl-cyclopropyl)-amide;-   [6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridin-2-yl]-(3,3-dimethyl-morpholin-4-yl)-methanone;-   [5-Cyclopropyl-6-(2-methyl-propane-1-sulfonyl)-pyridin-2-yl]-(2,2-dimethyl-pyrrolidin-1-yl)-methanone;-   [5-Cyclopropyl-6-(4-fluoro-benzyl)-pyridin-2-yl]-(4,4-dimethyl-oxazolidin-3-yl)-methanone;-   [6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridin-2-yl]-((1S,5R)-1,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct-6-yl)-methanone;-   [6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridin-2-yl]-((S)-4,4-difluoro-2-hydroxymethyl-pyrrolidin-1-yl)-methanone;-   (4-Aza-spiro[2.4]hept-4-yl)-[6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridin-2-yl]-methanone;-   [6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridin-2-yl]-(1S,4S)-2-thia-5-aza-bicyclo[2.2.1]hept-5-yl-methanone;-   (S)-1-(5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carbonyl)-4,4-difluoro-pyrrolidine-2-carboxylic    acid amide;-   (−)-1-[6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carbonyl]-4,4-dimethyl-pyrrolidine-2-carboxylic    acid amide;-   (5-Aza-spiro[3.4]oct-5-yl)-[6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridin-2-yl]-methanone;-   [6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridin-2-yl]-(1,1-difluoro-5-aza-spiro[2.4]hept-5-yl)-methanone;-   (5-Aza-spiro[2.4]hept-5-yl)-[6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridin-2-yl]-methanone;-   1-[5-Cyclopropyl-6-(4-fluoro-benzyl)-pyridine-2-carbonyl]-1,8-diaza-spiro[4.5]decane-8-carboxylic    acid tert-butyl ester; and-   (−)-3-(5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carbonyl)-1,1-dioxo-1λ6-thiazolidine-4-carboxylic    acid amide.

The invention also relates in particular to a compound selected from:

-   3-[6-(Cyclopropylmethoxy)-5-(3,3-difluoroazetidin-1-yl)pyridine-2-carbonyl]-1,1-dioxo-1,3-thiazolidine-4-carboxamide;-   (−)-3-[6-(Cyclopropylmethoxy)-5-(3,3-difluoroazetidin-1-yl)pyridine-2-carbonyl]-1,1-dioxo-1,3-thiazolidine-4-carboxamide;-   (2S)-1-[6-(Cyclopropylmethoxy)-5-(1-hydroxycyclobutyl)pyridine-2-carbonyl]-4,4-difluoropyrrolidine-2-carboxamide;-   (2S)-1-[6-(Cyclopropylmethoxy)-5-(1-fluorocyclobutyl)pyridine-2-carbonyl]-4,4-difluoropyrrolidine-2-carboxamide;-   (2S)-1-[6-(Cyclopropylmethoxy)-5-(3,3-difluoroazetidin-1-yl)pyridine-2-carbonyl]-4-hydroxy-4-methylpyrrolidine-2-carboxamide;-   3-[6-(Cyclopropylmethoxy)-5-(1-fluorocyclobutyl)pyridine-2-carbonyl]-1,1-dioxo-1,3-thiazolidine-4-carboxamide;    and-   5-[6-(Cyclopropylmethoxy)-5-(3,3-difluoroazetidin-1-yl)pyridine-2-carbonyl]-5-azaspiro[2.4]heptane-6-carboxamide.-   (S)-1-[6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carbonyl]-4,4-difluoro-pyrrolidine-2-carboxylic    acid amide is a particular compound of formula (I).

The compounds of the present invention can be prepared, for example, bythe general synthetic procedures described below.

In the following schemes and description, R¹ to R⁴ have, unlessotherwise indicated, the meaning of R¹ to R⁴ as defined above.

Following the procedure according to scheme 1, compound AA (X=Cl, Br, I,trifluoromethanesulfonate; R′=H, methyl, ethyl, isopropyl, tert. butylor another suitable protecting group described for example in T. W.Greene et al., Protective Groups in Organic Chemistry, John Wiley andSons Inc. New York 1999, 3^(rd) edition) can be used as startingmaterial. AA is either commercially available, described in theliterature, can be synthesized by a person skilled in the art, can besynthesized as described in schemes 3 and 5 or as described in theexperimental part.

Compound AC can be prepared from AA by coupling a suitably substitutedaryl, heteroaryl or alkenyl metal species of formula AB (M is e.g. aboronic acid B(OH)₂ or a boronic acid pinacol ester) (step a),particularly an arylboronic acid or arylboronic acid ester in thepresence of a suitable catalyst, in particular a palladium catalyst andmore particularly palladium(II)acetate/triphenylphosphine mixtures orpalladium(II)chloride-dppf (1,1′-bis(diphenylphosphino)ferrocene)complexes and a base such as triethylamine, sodium carbonate orpotassium phosphate in an inert solvent such as dimethylformamide,toluene, tetrahydrofuran, acetonitrile and dimethoxyethane. Optionally,alkenyl containing R¹ residues can be transformed to the correspondingalkyl congeners AC using conditions described in the literature such ase.g. via a hydrogenation reaction using hydrogen gas in the presence ofa catalyst such as palladium on carbon in a solvent such as ethanol orethyl acetate particularly at ambient temperature.

The saponification of the ester of general formula AC(R′≠H) by methodswell known to the ones skilled in the art—using e.g. aqueous LiOH, NaOHor KOH in tetrahydrofuran/ethanol or another suitable solvent attemperatures between 0° C. and the reflux temperature of the solventemployed—leads to an acid of general formula II (step b).

Compound I can be prepared from II and the corresponding amine offormula III by suitable amide bond forming reactions (step c). Thesereactions are known in the art. For example coupling reagents likeN,N′-carbonyl-diimidazole (CDI), N,N′-dicyclohexylcarbodiimide (DCC),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI),1-[bis(dimethylamino)-methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxidehexafluorophosphate (HATU), 1-hydroxy-1,2,3-benzotriazole (HOBT),O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium tetrafluoroborate(TBTU), andO-benzotriazole-N,N,N′,N′-tetramethyl-uronium-hexafluoro-phosphate(HBTU) can be employed to affect such transformation. A convenientmethod is to use for example HBTU and a base, for exampleN-methylmorpholine in an inert solvent such as for exampledimethylformamide at room temperature.

Alternatively esters of general formula AA (R′≠H) can be saponified bymethods well known to the ones skilled in the art—using e.g. aqueousLiOH, NaOH or KOH in tetrahydrofuran/ethanol or another suitable solventat temperatures between 0° C. and the reflux temperature of the solventemployed—to give acids of general formula AD (step b′).

Compounds AE can be prepared from AD and the corresponding amine offormula III by suitable amide bond forming reactions (step c′). Thesereactions are known in the art. For example coupling reagents likeN,N′-carbonyl-diimidazole (CDI), N,N′-dicyclohexylcarbodiimide (DCC),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI),1-[bis(dimethylamino)-methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxidehexafluorophosphate (HATU), 1-hydroxy-1,2,3-benzotriazole (HOBT),O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium tetrafluoroborate(TBTU), andO-benzotriazole-N,N,N′,N′-tetramethyl-uronium-hexafluoro-phosphate(HBTU) can be employed to affect such transformation. A convenientmethod is to use for example HBTU and a base, for exampleN-methylmorpholine in an inert solvent such as for exampledimethylformamide at room temperature.

Compound I can be prepared from AE by coupling a suitably substitutedaryl, heteroaryl or alkenyl metal species of formula AB (M is e.g. aboronic acid B(OH)₂ or a boronic acid pinacol ester) (step a′),particularly an arylboronic acid or arylboronic acid ester in thepresence of a suitable catalyst, in particular a palladium catalyst andmore particularly palladium(II)acetate/triphenylphosphine mixtures orpalladium(II)chloride-dppf (1,1′-bis(diphenylphosphino)ferrocene)complexes and a base such as triethylamine, sodium carbonate orpotassium phosphate in an inert solvent such as dimethylformamide,toluene, tetrahydrofuran, acetonitrile and dimethoxyethane. Optionally,alkenyl containing R¹ residues can be transformed to the correspondingalkyl congeners AE using conditions described in the literature such ase.g. via a hydrogenation reaction using hydrogen gas in the presence ofa catalyst such as palladium on carbon in a solvent such as ethanol orethyl acetate particularly at ambient temperature.

If one of R³ and R⁴ in amides AE or I is equal to hydrogen, alkylationtowards the corresponding tertiary amides AE or I can be accomplishede.g. by conversion of secondary amide AE or I to its conjugated base bytreatment with e.g. sodium hydride in a solvent such as DMF andsubsequent alkylation e.g. with an alkyl halide preferentially atambient temperature, or by applying any other suitable method known to aperson skilled in the art.

Amines III are either commercially available, described in theliterature, can be synthesized by a person skilled in the art or asdescribed in the experimental part.

If one of the starting materials, compounds of formulae AA, AB, AE (withone of R³ and R⁴ being equal to hydrogen) III or I (with one of R³ andR⁴ being equal to hydrogen) contains one or more functional groups whichare not stable or are reactive under the reaction conditions of one ormore reaction steps, appropriate protecting groups (P) (as describede.g. in T. W. Greene et al., Protective Groups in Organic Chemistry,John Wiley and Sons Inc. New York 1999, 3^(rd) edition) can beintroduced before the critical step applying methods well known in theart. Such protecting groups can be removed at a later stage of thesynthesis using standard methods known in the art.

If one or more compounds of formulae AA to AE, II or III contain chiralcenters, picolines of formula I can be obtained as mixtures ofdiastereomers or enantiomers, which can be separated by methods wellknown in the art, e.g. (chiral) HPLC or crystallization. Racemiccompounds can e.g. be separated into their antipodes via diastereomericsalts by crystallization or by separation of the antipodes by specificchromatographic methods using either a chiral adsorbent or a chiraleluent.

Following the procedure according to scheme 2, compound BA (R′=H,methyl, ethyl, isopropyl, tert. butyl or another suitable protectinggroup described for example in T. W. Greene et al., Protective Groups inOrganic Chemistry, John Wiley and Sons Inc. New York 1999, 3^(rd)edition) can be used as starting material. BA is either commerciallyavailable, described in the literature or can be synthesized by a personskilled in the art.

Compound BB can be prepared from BA by oxidation with a suitableoxidizing reagent under conditions known to a person skilled in the art(step a), e.g. by treatment with 3-chloro perbenzoic acid indichloromethane at ambient temperature.

Conversion of compound BB to 6-chloro or 6-bromo-picoline AA′ (X=Cl, Br)can be achieved e.g. by treatment with phosphoryl trichloride ortribromide either without an additional solvent or in a suitable solventsuch as chloroform at temperatures between 20° C. and the boiling pointof the solvent, or by using other conditions known in the literature(step b).

6-Chloro- or bromo-picoline AA′ (X=Cl, Br) can be transformed tocompound BD by reaction with a suitably substituted primary or secondaryalcohol BC in the presence of a base, for example sodium hydride, withor without an inert solvent, for example dimethylformamide, attemperatures ranging from room temperature to the reflux temperature ofthe solvent, particularly at room temperature (step c).

Compound BD can be further elaborated to compound I by: i)saponification (for compounds BD with R′≠H) as described in step b ofscheme 1 (step d); ii) amide bond formation as described in step c ofscheme 1 (step e).

Alternatively, compound AA′ (R′=methyl, ethyl, isopropyl, tert. butyl oranother suitable protecting group described for example in T. W. Greeneet al., Protective Groups in Organic Chemistry, John Wiley and Sons Inc.New York 1999, 3^(rd) edition) can be: i) converted into its acidcongener AA′ (R′═H) as described in step b of scheme 1; ii) transformedinto the corresponding amide by treatment with amine III as described instep c of scheme 1; and iii) reacted with alcohol BC as described instep c to arrive at compound I.

If one of R³ and R⁴ in amide I is equal to hydrogen, alkylation towardsthe corresponding tertiary amide I can be accomplished e.g. byconversion of secondary amide I to its conjugated base by treatment withe.g. sodium hydride in a solvent such as DMF and subsequent alkylatione.g. with an alkyl halide preferentially at ambient temperature, or byapplying any other suitable method known to a person skilled in the art.

If one of the starting materials, compounds of formulae BA, BC, III or I(with one of R³ and R⁴ being equal to hydrogen), contains one or morefunctional groups which are not stable or are reactive under thereaction conditions of one or more reaction steps, appropriateprotecting groups (P) (as described e.g. in T. W. Greene et al.,Protective Groups in Organic Chemistry, John Wiley and Sons Inc. NewYork 1999, 3^(rd) edition) can be introduced before the critical stepapplying methods well known in the art. Such protecting groups can beremoved at a later stage of the synthesis using standard methods knownin the art.

If one or more compounds of formulae BA to BD, AA′, II or III containchiral centers, picolines of formula I can be obtained as mixtures ofdiastereomers or enantiomers, which can be separated by methods wellknown in the art, e.g. (chiral) HPLC or crystallization. Racemiccompounds can e.g. be separated into their antipodes via diastereomericsalts by crystallization or by separation of the antipodes by specificchromatographic methods using either a chiral adsorbent or a chiraleluent.

Following the procedure according to scheme 3, compound CA (R′=H,methyl, ethyl, isopropyl, tert. butyl or another suitable protectinggroup described for example in T. W. Greene et al., Protective Groups inOrganic Chemistry, John Wiley and Sons Inc. New York 1999, 3^(rd)edition) can be used as starting material. CA is either commerciallyavailable (e.g. for R′=methyl: 5-bromo-6-chloro-pyridine-2-carboxylicacid methyl ester CAN 1214353-79-3), described in the literature or canbe synthesized by a person skilled in the art.

Compound AA″ can be prepared from CA by coupling a suitably substitutedaryl, heteroaryl or alkenyl metal species of formula CB (M is e.g. atrifluoroborate [BF₃]⁻K⁺, a boronic acid B(OH)₂ or a boronic acidpinacol ester) (step a), e.g. an organotrifluoroborate potassium salt inthe presence of a palladium catalyst such aspalladium(II)acetate/butyl-1-adamantylphosphine and a base such ascesium carbonate in an inert solvent such as toluene at temperaturesbetween 50° C. and the boiling temperature of the solvent, or anarylboronic acid or arylboronic acid ester in the presence of a suitablecatalyst, in particular a palladium catalyst and more particularlypalladium(II)acetate/triphenylphosphine mixtures orpalladium(II)chloride-dppf (1,1′-bis(diphenylphosphino)ferrocene)complexes and a base such as triethylamine, sodium carbonate orpotassium phosphate in an inert solvent such as dimethylformamide,toluene, tetrahydrofuran, acetonitrile or dimethoxyethane. Optionally,compound CB can also be an amine or amide which is coupled to CA bymethods well known to a person skilled in the art, e.g. using apalladium catalyst such astris(dibenzylideneacetone)dipalladium/dimethylbisdiphenyl-phosphinoxantheneand a base such as cesium carbonate in a solvent such as 1,4-dioxane,preferentially at the boiling point of the solvent. Alternatively,compound CB can also be a sulfonamide which undergoes a copper(I)mediated reaction with CA to form AA″ following procedures described inthe literature, e.g. using copper(I) iodide and1,3-di(pyridin-2-yl)propane-1,3-dione in the presence of a base such aspotassium carbonate in a solvent such as dimethylformamide at elevatedtemperatures preferentially at the boiling point of the solvent.Optionally, alkenyl containing R² residues can be transformed to thecorresponding alkyl congeners AA″ using conditions described in theliterature such as e.g. a hydrogenation reaction using hydrogen gas inthe presence of a catalyst such as palladium on carbon in a solvent suchas ethanol or ethyl acetate particularly at ambient temperature.

Compound AA″ can be further elaborated to compound I by: i) reactionwith compound BC to form compound BD as described in step c of scheme 2;ii) saponification as described in step b of scheme 1; and iii) amidebond formation as described in step c of scheme 1.

Furthermore, compound CA can be converted into compound CC by treatmentwith compound BC as described in step c of scheme 2 (step b).

Subsequent transformation of compound CC into compound BD can beachieved as discussed for the conversion of CA into AA″ (step a).

Compound BD can be further elaborated to compound I by: i)saponification as described in step b of scheme 1; ii) amide bondformation as described in step c of scheme 1.

Alternatively, compound CC(R′=methyl, ethyl, isopropyl, tert. butyl oranother suitable protecting group described for example in T. W. Greeneet al., Protective Groups in Organic Chemistry, John Wiley and Sons Inc.New York 1999, 3^(rd) edition) can be: i) converted into its acidcongener CC(R′═H) as described in step b of scheme 1; ii) transformedinto the corresponding amide CD by treatment with amine III as describedin step c of scheme 1; and iii) reacted with CB as described in step ato arrive at compound I.

In addition, compounds of formula I with R¹ being an alkylsulfonylresidue can be synthesized using the following reaction sequence: i)Reaction of compound CA (e.g. for R′═H:5-bromo-6-chloro-pyridine-2-carboxylic acid; CAN 959958-25-9) with athiol BC to yield thioether CC, e.g. in the presence of a base such ascesium carbonate in a solvent such as DMSO, preferentially attemperatures between 100 and 150° C.; ii) conversion of thioethersCC(R¹═S-Alkyl) to its corresponding sulfonyl congeners CC(R¹═S(O)₂—Alkyl), e.g. by using an oxidizing reagent such as 3-chlorobenzoperoxoicacid in a solvent such as dichloromethane, preferentially at ambienttemperature; iii) transformation of sulfonyl derivatives CC intocompound BD as discussed for the conversion of CA into AA″ (step a); andiv) further elaboration to sulfonyl derivative I via saponification asdescribed in step b of scheme 1 followed by an amide bond formation asdescribed in step c of scheme 1. Optionally, the row order of thereaction sequence can be interchanged.

Furthermore, compound I can also be synthesized applying the followingreaction sequence: i) saponification of compound CA (R′=methyl, ethyl,isopropyl, tert. butyl or another suitable protecting group describedfor example in T. W. Greene et al., Protective Groups in OrganicChemistry, John Wiley and Sons Inc. New York 1999, 3^(rd) edition) toits acid congener CC(R′═H) as described in step b of scheme 1; ii)conversion to the corresponding amide by treatment with amine III asdescribed in step c of scheme 1; iii) reaction with compound CB asdescribed in step a; and iv) reaction with compound BC as described instep c. Optionally step iii) and step iv) can be interchanged.

If one of R³ and R⁴ in amides CD or I is equal to hydrogen, alkylationtowards the corresponding tertiary amides CD or I can be accomplishede.g. by conversion of secondary amide CD or I to its conjugated base bytreatment with e.g. sodium hydride in a solvent such as DMF andsubsequent alkylation e.g. with an alkyl halide preferentially atambient temperature, or by applying any other suitable method known to aperson skilled in the art.

If one of the starting materials, compounds of formulae CA, CB, CD (withone of R³ and R⁴ being equal to hydrogen), BC, III or I (with one of R³and R⁴ being equal to hydrogen) contains one or more functional groupswhich are not stable or are reactive under the reaction conditions ofone or more reaction steps, appropriate protecting groups (P) (asdescribed e.g. in T. W. Greene et al., Protective Groups in OrganicChemistry, John Wiley and Sons Inc. New York 1999, 3^(rd) edition) canbe introduced before the critical step applying methods well known inthe art. Such protecting groups can be removed at a later stage of thesynthesis using standard methods known in the art.

If one or more compounds of formulae CA, CB, BC or III contain chiralcenters, picolines of formula AA′, BD and I can be obtained as mixturesof diastereomers or enantiomers, which can be separated by methods wellknown in the art, e.g. (chiral) HPLC or crystallization. Racemiccompounds can e.g. be separated into their antipodes via diastereomericsalts by crystallization or by separation of the antipodes by specificchromatographic methods using either a chiral adsorbent or a chiraleluent.

Following the procedure according to scheme 4, compound CC(R′=H, methyl,ethyl, isopropyl, tert. butyl or another suitable protecting groupdescribed for example in T. W. Greene et al., Protective Groups inOrganic Chemistry, John Wiley and Sons Inc. New York 1999, 3^(rd)edition) can be used as starting material. CC is either commerciallyavailable, described in the literature, can be synthesized by methodsdescribed in scheme 3 or by other methods known to a person skilled inthe art.

Compound BD can be prepared from CC by coupling a suitably substitutedaryl, heteroaryl or alkenyl metal species of formula CB (M is e.g. atrifluoroborate [BF₃]⁻K⁺, a boronic acid B(OH)₂ or a boronic acidpinacol ester) (step a), e.g. an organotrifluoroborate potassium salt inthe presence of a palladium catalyst such aspalladium(II)acetate/butyl-1-adamantylphosphine and a base such ascesium carbonate in an inert solvent such as toluene at temperaturesbetween 50° C. and the boiling temperature of the solvent, or anarylboronic acid or arylboronic acid ester in the presence of a suitablecatalyst, in particular a palladium catalyst and more particularlypalladium(II)acetate/triphenylphosphine mixtures orpalladium(II)chloride-dppf (1,1′-bis(diphenylphosphino)ferrocene)complexes and a base such as triethylamine, sodium carbonate orpotassium phosphate in an inert solvent such as dimethylformamide,toluene, tetrahydrofuran, acetonitrile and dimethoxyethane. Optionally,alkenyl containing R² residues can be transformed to the correspondingalkyl congeners BD using conditions described in the literature such ase.g. a hydrogenation reaction using hydrogen gas in the presence of acatalyst such as palladium on carbon in a solvent such as ethanol orethyl acetate particularly at ambient temperature.

Alternatively, compound CC can be converted to amino derivatives BD bytreatment with an amine BC applying methods well known in the art (stepb), for example using a palladium promoted amination withpalladium(II)acetate/2-(dicyclohexylphosphino) biphenyl in the presenceof a base such as potassium carbonate in dioxane under reflux conditionsor by using tris(dibenzylideneacetone)dipalladium/rac-BINAP(2,2′-bis(diphenylphosphino)-1,1′-binaphthyl) in the presence of a basesuch as cesium carbonate in toluene at 100° C.

Compound CC can furthermore be reacted with ketone DA (R^(2′)=alkyl,cycloalkyl, or oxyoxetanyl) to obtain compound BD following proceduresknown to a person skilled in the art, e.g.: i) treatment with n-butyllithium in a solvent such as tetrahydrofuran at a temperature of −78°C.; ii) addition of a ketone DA or optionally another suitableelectrophile at temperatures between −78° C. and ambient temperature(step c).

Compound BD can be further elaborated to compound I by: i)saponification as described in step b of scheme 1; ii) amide bondformation as described in step c of scheme 1.

If one of the starting materials, compounds of formulae CC, CB, BC orDA, contains one or more functional groups which are not stable or arereactive under the reaction conditions of one or more reaction steps,appropriate protecting groups (P) (as described e.g. in T. W. Greene etal., Protective Groups in Organic Chemistry, John Wiley and Sons Inc.New York 1999, 3^(rd) edition) can be introduced before the criticalstep applying methods well known in the art. Such protecting groups canbe removed at a later stage of the synthesis using standard methodsknown in the art.

If one or more compounds of formulae CC, CB, BC or DA, contain chiralcenters, picolines of formula BD can be obtained as mixtures ofdiastereomers or enantiomers, which can be separated by methods wellknown in the art, e.g. (chiral) HPLC or crystallization. Racemiccompounds can e.g. be separated into their antipodes via diastereomericsalts by crystallization or by separation of the antipodes by specificchromatographic methods using either a chiral adsorbens or a chiraleluent.

Following the procedure according to scheme 5, compound GA (X=Cl, Br, I,trifluoromethanesulfonate; R′=H, methyl, ethyl, isopropyl, tert. butylor another suitable protecting group described for example in T. W.Greene et al., Protective Groups in Organic Chemistry, John Wiley andSons Inc. New York 1999, 3^(rd) edition) can be used as startingmaterial. GA is either commercially available, described in theliterature or can be synthesized by a person skilled in the art.

Compound BA can be prepared from EA by coupling a suitably substitutedaryl, heteroaryl or alkenyl metal species of formula CB (M is e.g. atrifluoroborate [BF₃]⁻K⁺, a boronic acid B(OH)₂ or a boronic acidpinacol ester) (step a), e.g. an organotrifluoroborate potassium salt inthe presence of a palladium catalyst such aspalladium(II)acetate/butyl-1-adamantylphosphine and a base such ascesium carbonate in an inert solvent such as toluene at temperaturesbetween 50° C. and the boiling temperature of the solvent, or anarylboronic acid or arylboronic acid ester in the presence of a suitablecatalyst, in particular a palladium catalyst and more particularlypalladium(II)acetate/triphenylphosphine mixtures orpalladium(II)chloride-dppf (1,1′-bis(diphenylphosphino)ferrocene)complexes and a base such as triethylamine, sodium carbonate orpotassium phosphate in an inert solvent such as dimethylformamide,toluene, tetrahydrofuran, acetonitrile and dimethoxyethane. Optionally,compound CB can also be an amine or amide which is coupled to EA bymethods well known to a person skilled in the art, e.g. using apalladium catalyst such astris(dibenzylideneacetone)dipalladium/dimethylbisdiphenyl-phosphinoxantheneand a base such as cesium carbonate in a solvent such as 1,4-dioxanepreferentially at the boiling point of the solvent. Optionally, alkenylcontaining R² residues can be transformed to the corresponding alkylcongeners BA using conditions described in the literature such as e.g. ahydrogenation reaction using hydrogen gas in the presence of a catalystsuch as palladium on carbon in a solvent such as ethanol or ethylacetate particularly at ambient temperature.

Compound BB can be prepared from BA by oxidation with a suitableoxidizing reagent as described in step a of scheme 2 (step b).

Conversion of compound BB to 6-chloro- or 6-bromo-picoline AA′ (X=Cl,Br) can be achieved as described in step b of scheme 2 (step c).

Compound AC can be prepared from AA′ by coupling a suitably substitutedaryl, heteroaryl or alkenyl metal species of formula AB (M is e.g. aboronic acid B(OH)₂ or a boronic acid pinacol ester) (step d),particularly an arylboronic acid or arylboronic acid ester in thepresence of a suitable catalyst, in particular a palladium catalyst andmore particularly palladium(II)acetate/triphenylphosphine mixtures orpalladium(II)chloride-dppf (1,1′-bis(diphenylphosphino)ferrocene)complexes and a base such as triethylamine, sodium carbonate orpotassium phosphate in an inert solvent such as dimethylformamide,toluene, tetrahydrofuran, acetonitrile and dimethoxyethane. Optionally,alkenyl containing R¹ residues can be transformed to the correspondingalkyl congeners AC using conditions described in the literature such ase.g. a hydrogenation reaction using hydrogen gas in the presence of acatalyst such as palladium on carbon in a solvent such as ethanol orethyl acetate particularly at ambient temperature.

Compound AC can be further elaborated to compound I by: i)saponification as described in step b of scheme 1 (step e); ii) amidebond formation as described in step c of scheme 1 (step f).

If one of R³ and R⁴ in amide I is equal to hydrogen, alkylation towardsthe corresponding tertiary amide I can be accomplished e.g. byconversion of secondary amide I to its conjugated base by treatment withe.g. sodium hydride in a solvent such as DMF and subsequent alkylatione.g. with an alkyl halide preferentially at ambient temperature, or byapplying any other suitable method known to a person skilled in the art.

If one of the starting materials, compounds of formulae EA, CB, AB, IIIor I (with one of R³ and R⁴ being equal to hydrogen) contains one ormore functional groups which are not stable or are reactive under thereaction conditions of one or more reaction steps, appropriateprotecting groups (P) (as described e.g. in T. W. Greene et al.,Protective Groups in Organic Chemistry, John Wiley and Sons Inc. NewYork 1999, 3^(rd) edition) can be introduced before the critical stepapplying methods well known in the art. Such protecting groups can beremoved at a later stage of the synthesis using standard methods knownin the art.

If one or more compounds of formulae EA, CB, BA, BB, AA′, AB, AC, II orIII contain chiral centers, picolines of formula I can be obtained asmixtures of diastereomers or enantiomers, which can be separated bymethods well known in the art, e.g. (chiral) HPLC or crystallization.Racemic compounds can e.g. be separated into their antipodes viadiastereomeric salts by crystallization or by separation of theantipodes by specific chromatographic methods using either a chiraladsorbent or a chiral eluent.

Following the procedure according to scheme 6, compound FA can be usedas starting material. FA is either commercially available, described inthe literature or can be synthesized by a person skilled in the art.

Compound FB can be prepared from FA by oxidation with a suitableoxidizing reagent under conditions known to a person skilled in the art(step a), e.g. by treatment with 3-chloro perbenzoic acid indichloromethane at ambient temperature.

Conversion of compound FB to 6-chloro or 6-bromo compound FC (X=Cl, Br)can be achieved e.g. by treatment with phosphoryl trichloride ortribromide either without an additional solvent or in a suitable solventsuch as chloroform at temperatures between 20° C. and the boiling pointof the solvent or by using other conditions known in the literature(step b).

Hydrolysis of compound FC leads to picoline FD and can be performedunder acidic or basic conditions known to a person skilled in the art,e.g. by treatment with an aqueous solution of sodium hydroxide at 100°C. (step c).

Compound II can be prepared from FD by coupling a suitably substitutedaryl, heteroaryl or alkenyl metal species of formula AB (M is e.g. aboronic acid B(OH)₂ or a boronic acid pinacol ester) (step d) asdescribed in step d of scheme 6. Optionally, alkenyl containing R¹residues can be transformed to the corresponding alkyl congeners IIusing conditions described in the literature such as e.g. ahydrogenation reaction using hydrogen gas in the presence of a catalystsuch as palladium on carbon in a solvent such as ethanol or ethylacetate particularly at ambient temperature. In cases where the acidgroup of compound FD is not compatible with the conditions applied tointroduce the R¹ residue, suitable protecting groups such as esterprotecting groups e.g. a methyl ester can be introduced prior to step dand removed at a later point of the synthesis. Protecting groupintroduction and removal can be carried out by suitable methods known inthe art (for more details see T. W. Greene et al., Protective Groups inOrganic Chemistry, John Wiley and Sons Inc. New York 1999, 3^(rd)edition).

Further conversion of compound II to compound I can be done by applyingamide bond formation conditions as depicted in step c of scheme 1 (stepe).

If one of R³ and R⁴ in amide I is equal to hydrogen, alkylation towardsthe corresponding tertiary amide I can be accomplished e.g. byconversion of secondary amide I to its conjugated base by treatment withe.g. sodium hydride in a solvent such as DMF and subsequent alkylatione.g. with an alkyl halide preferentially at ambient temperature, or byapplying any other suitable method known to a person skilled in the art.

If one of the starting materials, compounds of formulae FA, AB, III or I(with one of R³ and R⁴ being equal to hydrogen) contains one or morefunctional groups which are not stable or are reactive under thereaction conditions of one or more reaction steps, appropriateprotecting groups (P) (as described e.g. in T. W. Greene et al.,Protective Groups in Organic Chemistry, John Wiley and Sons Inc. NewYork 1999, 3^(rd) edition) can be introduced before the critical stepapplying methods well known in the art. Such protecting groups can beremoved at a later stage of the synthesis using standard methods knownin the art.

If one or more compounds of formulae FA, to FD, AB, II or III containchiral centers, picolines of formula I can be obtained as mixtures ofdiastereomers or enantiomers, which can be separated by methods wellknown in the art, e.g. (chiral) HPLC or crystallization. Racemiccompounds can e.g. be separated into their antipodes via diastereomericsalts by crystallization or by separation of the antipodes by specificchromatographic methods using either a chiral adsorbent or a chiraleluent.

Following the procedure according to scheme 7, commercially available5-bromo-6-methyl-pyridine-2-carbonitrile GA (CAN 1173897-86-3) can beused as starting material. In scheme 7, R¹ is benzyl or halobenzyl;R^(1′) is phenyl or halophenyl.

Compound GB can be prepared from GA by treatment with compound CB (M ise.g. a trifluoroborate [BF₃]⁻K⁺, a boronic acid B(OH)₂ or a boronic acidpinacol ester) as described in step a of scheme 5 (step a).

Further transformation of GB to GC can be achieved by oxidation with asuitable oxidizing reagent as described in step a of scheme 6 (step b).

Conversion of N-oxide GC to alcohol GD can be performed under conditionswell known to a person skilled in the art, e.g. by reaction withtrifluoroacetic acid anhydride in a solvent such as dichloromethanepreferentially at ambient temperature and subsequent treatment with abase such as sodium hydroxide (step c).

Reactions how to convert alcohol GD into compound GE containing aleaving group (Y=Cl, Br or another suitable leaving group) are welldescribed in the literature and known to those skilled in the art (stepd). For example alcohol GD can be transformed to compound GE with Y═Brby reaction with carbon tetrabromide and triphenylphosphine in a solventsuch as tetrahydrofuran at temperatures between 0° C. and the boilingpoint of the solvent, preferentially at 40° C.

Conversion of compound GE to compound GF can e.g. be accomplished bycoupling a suitably substituted aryl metal species of formula AB′ (M ise.g. a boronic acid B(OH)₂ or a boronic acid pinacol ester),particularly an arylboronic acid or arylboronic acid ester in thepresence of a suitable catalyst, in particular a palladium catalyst andmore particularly palladium(II)acetate/triphenylphosphine mixtures orpalladium(II)chloride-dppf (1,1′-bis(diphenylphosphino)ferrocene)complexes and a base such as triethylamine, cesium carbonate orpotassium phosphate in an inert solvent such as dimethylformamide,toluene, tetrahydrofuran and 1,4-dioxane (step e).

Nitrile GF can be hydrolyzed to acid II applying the method described instep c of scheme 6 (step f).

Further conversion of compound II to compound I can be done by applyingamide bond formation conditions as depicted in step c of scheme 1 (stepe).

If one of R³ and R⁴ in amide I is equal to hydrogen, alkylation towardsthe corresponding tertiary amide I can be accomplished e.g. byconversion of secondary amide I to its conjugated base by treatment withe.g. sodium hydride in a solvent such as DMF and subsequent alkylatione.g. with an alkyl halide preferentially at ambient temperature, or byapplying any other suitable method known to a person skilled in the art.

If one of the starting materials, compounds of formulae GA, CB, AB′, IIIor I (with one of R³ and R⁴ being equal to hydrogen) contains one ormore functional groups which are not stable or are reactive under thereaction conditions of one or more reaction steps, appropriateprotecting groups (P) (as described e.g. in T. W. Greene et al.,Protective Groups in Organic Chemistry, John Wiley and Sons Inc. NewYork 1999, 3^(rd) edition) can be introduced before the critical stepapplying methods well known in the art. Such protecting groups can beremoved at a later stage of the synthesis using standard methods knownin the art.

If one or more compounds of formulae GA to GF, CB, AB′, II or IIIcontain chiral centers, picolines of formula I can be obtained asmixtures of diastereomers or enantiomers, which can be separated bymethods well known in the art, e.g. (chiral) HPLC or crystallization.Racemic compounds can e.g. be separated into their antipodes viadiastereomeric salts by crystallization or by separation of theantipodes by specific chromatographic methods using either a chiraladsorbent or a chiral eluent.

The invention also relates to a process for the preparation of acompound of formula (I) comprising one of the following steps:

(a) the reaction of a compound of formula (A)

in the presence of NHR³R⁴, an amide bond forming coupling agent and abase; or

(b) the reaction of a compound of formula (B)

with a compound of formula R⁴—X;

wherein R¹ to R⁴ are as defined above and X is a leaving group.

X is for example Cl, Br or I. X can be any other suitable leaving groupknown to a person skilled in the art.

Compounds of formula (A) or NHR³R⁴ may contain functional groups thatwould interfere with the coupling procedures described for the amidecoupling step. In this case it is understood that (A) or NHR³R⁴ need tobe suitably protected by methods known in the art before conducting theamide coupling procedure and compounds need to be deprotected after thecoupling step by methods known in the art to deliver compounds offormula (I).

Suitable coupling agents are for example N,N′-carbonyldiimidazole (CDI),N,N′-dicyclohexylcarbodiimide (DCC),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI),1-[bis(dimethylamino)-methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxidehexafluorophosphate (HATU), 1-hydroxy-1,2,3-benzotriazole (HOBT),O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium tetrafluoroborate(TBTU) orO-benzotriazole-N,N,N′,N′-tetramethyl-uronium-hexafluoro-phosphate(HBTU). A particular coupling agent is HBTU.

Examples of suitable bases include triethylamine, diisopropylethylamineand particularly N-methylmorpholine.

The reaction temperature is for example room temperature.

A convenient method is to use for example HBTU and a base, for exampleN-methylmorpholine, in an inert solvent such as for exampledimethylformamide, in particular at room temperature.

The invention also relates in particular to:

The use of a compound of formula (I) for the treatment or prophylaxis ofpain, atherosclerosis, age-related macular degeneration, diabeticretinopathy, glaucoma, retinal vein occlusion, retinopathy ofprematurity, ocular ischemic syndrome, geographic atrophy, diabetesmellitus, inflammation, inflammatory bowel disease, ischemia-reperfusioninjury, acute liver failure, liver fibrosis, lung fibrosis, kidneyfibrosis, systemic fibrosis, acute allograft rejection, chronicallograft nephropathy, diabetic nephropathy, glomerulonephropathy,cardiomyopathy, heart failure, myocardial ischemia, myocardialinfarction, systemic sclerosis, thermal injury, burning, hypertrophicscars, keloids, gingivitis pyrexia, liver cirrhosis or tumors,regulation of bone mass, neurodegeneration, amyotrophic lateralsclerosis, stroke, transient ischemic attack or uveitis;

The use of a compound according of formula (I) for the preparation of amedicament for the treatment or prophylaxis of pain, atherosclerosis,age-related macular degeneration, diabetic retinopathy, glaucoma,retinal vein occlusion, retinopathy of prematurity, ocular ischemicsyndrome, geographic atrophy, diabetes mellitus, inflammation,inflammatory bowel disease, ischemia-reperfusion injury, acute liverfailure, liver fibrosis, lung fibrosis, kidney fibrosis, systemicfibrosis, acute allograft rejection, chronic allograft nephropathy,diabetic nephropathy, glomerulonephropathy, cardiomyopathy, heartfailure, myocardial ischemia, myocardial infarction, systemic sclerosis,thermal injury, burning, hypertrophic scars, keloids, gingivitispyrexia, liver cirrhosis or tumors, regulation of bone mass,neurodegeneration, amyotrophic lateral sclerosis, stroke, transientischemic attack or uveitis;

A compound of formula (I) for the treatment or prophylaxis of pain,atherosclerosis, age-related macular degeneration, diabetic retinopathy,glaucoma, retinal vein occlusion, retinopathy of prematurity, ocularischemic syndrome, geographic atrophy, diabetes mellitus, inflammation,inflammatory bowel disease, ischemia-reperfusion injury, acute liverfailure, liver fibrosis, lung fibrosis, kidney fibrosis, systemicfibrosis, acute allograft rejection, chronic allograft nephropathy,diabetic nephropathy, glomerulonephropathy, cardiomyopathy, heartfailure, myocardial ischemia, myocardial infarction, systemic sclerosis,thermal injury, burning, hypertrophic scars, keloids, gingivitispyrexia, liver cirrhosis or tumors, regulation of bone mass,neurodegeneration, amyotrophic lateral sclerosis, stroke, transientischemic attack or uveitis; and

A method for the treatment or prophylaxis of pain, atherosclerosis,age-related macular degeneration, diabetic retinopathy, glaucoma,retinal vein occlusion, retinopathy of prematurity, ocular ischemicsyndrome, geographic atrophy, diabetes mellitus, inflammation,inflammatory bowel disease, ischemia-reperfusion injury, acute liverfailure, liver fibrosis, lung fibrosis, kidney fibrosis, systemicfibrosis, acute allograft rejection, chronic allograft nephropathy,diabetic nephropathy, glomerulonephropathy, cardiomyopathy, heartfailure, myocardial ischemia, myocardial infarction, systemic sclerosis,thermal injury, burning, hypertrophic scars, keloids, gingivitispyrexia, liver cirrhosis or tumors, regulation of bone mass,neurodegeneration, amyotrophic lateral sclerosis, stroke, transientischemic attack or uveitis, which method comprises administering aneffective amount of a compound of formula (I) to a patient in needthereof.

The invention particularly relates to a compound of formula (I) for thetreatment or prophylaxis of ischemia, reperfusion injury, liver fibrosisor kidney fibrosis, in particular ischemia or reperfusion injury.

The invention further particularly relates to a compound of formula (I)for the treatment or prophylaxis of diabetic retinopathy, retinal veinocclusion or uveitis.

The invention is further directed to a compound of formula (I), whenmanufactured according to a process according to the invention.

Another embodiment of the invention provides a pharmaceuticalcomposition or medicament containing a compound of the invention and atherapeutically inert carrier, diluent or excipient, as well as a methodof using the compounds of the invention to prepare such composition andmedicament. In one example, the compound of formula (I) may beformulated by mixing at ambient temperature at the appropriate pH, andat the desired degree of purity, with physiologically acceptablecarriers, i.e., carriers that are non-toxic to recipients at the dosagesand concentrations employed into a galenical administration form. The pHof the formulation depends mainly on the particular use and theconcentration of compound, but preferably ranges anywhere from about 3to about 8. In one example, a compound of formula (I) is formulated inan acetate buffer, at pH 5. In another embodiment, the compound offormula (I) is sterile. The compound may be stored, for example, as asolid or amorphous composition, as a lyophilized formulation or as anaqueous solution.

Compositions are formulated, dosed, and administered in a fashionconsistent with good medical practice. Factors for consideration in thiscontext include the particular disorder being treated, the particularmammal being treated, the clinical condition of the individual patient,the cause of the disorder, the site of delivery of the agent, the methodof administration, the scheduling of administration, and other factorsknown to medical practitioners.

The compounds of the invention may be administered by any suitablemeans, including oral, topical (including buccal and sublingual),rectal, vaginal, transdermal, parenteral, subcutaneous, intraperitoneal,intrapulmonary, intradermal, intrathecal and epidural and intranasal,and, if desired for local treatment, intralesional administration.Parenteral infusions include intramuscular, intravenous, intraarterial,intraperitoneal, or subcutaneous administration. The compounds of theinvention may be administered in particular by intravitrealadministration.

The compounds of the present invention may be administered in anyconvenient administrative form, e.g., tablets, powders, capsules,solutions, dispersions, suspensions, syrups, sprays, suppositories,gels, emulsions, patches, etc. Such compositions may contain componentsconventional in pharmaceutical preparations, e.g., diluents, carriers,pH modifiers, sweeteners, bulking agents, and further active agents.

A typical formulation is prepared by mixing a compound of the presentinvention and a carrier or excipient. Suitable carriers and excipientsare well known to those skilled in the art and are described in detailin, e.g., Ansel, Howard C., et al., Ansel's Pharmaceutical Dosage Formsand Drug Delivery Systems. Philadelphia: Lippincott, Williams & Wilkins,2004; Gennaro, Alfonso R., et al. Remington: The Science and Practice ofPharmacy. Philadelphia: Lippincott, Williams & Wilkins, 2000; and Rowe,Raymond C. Handbook of Pharmaceutical Excipients. Chicago,Pharmaceutical Press, 2005. The formulations may also include one ormore buffers, stabilizing agents, surfactants, wetting agents,lubricating agents, emulsifiers, suspending agents, preservatives,antioxidants, opaquing agents, glidants, processing aids, colorants,sweeteners, perfuming agents, flavoring agents, diluents and other knownadditives to provide an elegant presentation of the drug (i.e., acompound of the present invention or pharmaceutical composition thereof)or aid in the manufacturing of the pharmaceutical product (i.e.,medicament).

The invention will now be illustrated by the following examples whichhave no limiting character.

EXAMPLES Abbreviations

BINAP=2,2′-Bis(diphenylphosphino)-1,1′-binaphthyl; CAN=CAS RegistryNumber; DCM=dichloromethane; DIEA=N-ethyl-N-isopropylpropan-2-amine;DMF=dimethylformamide; DMSO=dimethyl-sulfoxide;dppf=1,1′-bis(diphenylphosphino)ferrocene; EI=electron ionization;ESI=electrospray; EtOAc=ethyl acetate; HPLC=LC=high performance liquidchromatography; m-CPBA=meta-chloroperoxybenzoic acid; MS=massspectrometry; NMR=nuclear magnetic resonance;TBTU=O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyl-uronium-tetrafluoroborate;TBME=methyl tert-butylether,TEMPO=(2,2,6,6-tetramethylpiperidin-1-yl)oxidanyl; THF=tetrahydrofuran;tlc=thin layer chromatography.

Example 16-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylicacid tert-butyl-methyl-amide a)6-Chloro-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acidmethyl ester

Under a nitrogen atmosphere a mixture of methyl5-bromo-6-chloro-pyridine-2-carboxylic acid methyl ester (Example 3 a, 2g, 8 mmol), 3,3-difluoroazetidine hydrochloride (CAN 288315-03-7, 1 g, 8mmol), tris(dibenzylideneacetone)dipalladium (CAN 51364-51-3, 0.16 g,0.16 mmol), (R)-(+)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (CAN76189-55-4, 0.19 g, 0.32 mmol) and cesium carbonate (3.9 g, 12 mmol) intoluene (50 mL) was stirred at 110° C. overnight. After concentration,the residue was partitioned between water (50 mL) and ethyl acetate (40mL), the aqueous phase was extracted with ethyl acetate (2×40 mL). Thecombined organic phase was washed with brine (40 mL), dried overanhydrous sodium sulfate, filtered and concentrated to give a residue.The residue was purified by column chromatography (silica gel, 20 g, 10%ethyl acetate in petroleum ether) to give the target compound (0.44 g,21%) as light-yellow solid; MS (EI): m/e=263.0 [MH⁺].

b)6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylicacid

Sodium hydride (0.29 g, 8.4 mmol) was added in portion to a solution ofcyclopropylmethanol (CAN 2516-33-8, 0.36 g, 5 mmol) in DMF (3 mL) andthe mixture was stirred at room temperature for 2 h.6-Chloro-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acidmethyl ester (0.44 g, 1.68 mmol) was added to the mixture and theresulting solution was stirred at 110° C. overnight. Afterconcentration, water (20 mL) was added to the residue and the solutionwas acidified with an aqueous solution of hydrochloride (6 N), thenextracted with ethyl acetate (2×20 mL). The combined organic phase waswashed with brine (20 mL), dried over anhydrous sodium sulfate, filteredand concentrated to give a residue. The residue was purified by prep-TLC(eluting with 50% ethyl acetate in petroleum ether) to give the targetcompound (0.07 g, 14%); MS (EI): m/e=285.1 [MH⁺].

c)6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylicacid tert-butyl-methyl-amide

A solution of6-(cyclopropylmethoxy)-5-(3,3-difluoroazetidin-1-yl)picolinic acid (10mg, 35 μmol), N,2-dimethylpropan-2-amine (CAN 94896-77-2, 3.68 mg, 42.2μmol), 1-hydroxybenzotriazole hydrate (11 mg, 70 μmol),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (12 mg, 70μmol) and DIEA (18.2 mg, 24 μl, 141 μmol) in DMF (157 μL) was stirredfor 2 d at ambient temperature. The reaction mixture was poured ontoice-water/1N HCl (20 mL), extracted with EtOAc (2×30 mL) and washed withice-water/brine (20 mL). The organic layers were combined, dried overNa₂SO₄ and concentrated in vacuo to give 24 mg of a yellow oil which waspurified by TLC (silica gel, Heptane/EtOAc 1:1, elution with DCM/EtOAc1:1) to give the title compound (11 mg, 89%) as light yellow oil; MS(EI): m/e=354.5 [MH⁺].

Example 26-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylicacid dimethylamide

In analogy to the procedure described in Example 47 b),6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylicacid (Example 1 b)) was reacted with dimethylamine hydrochloride (CAN506-59-2) in the presence of TBTU and DIEA to give the title compound aslight yellow oil; MS (EI): m/e=312.4 [MH⁺].

Example 3 5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acidtert-butyl-methyl-amide a) 5-Bromo-6-chloro-pyridine-2-carboxylic acidmethyl ester

A mixture of 5-bromo-pyridine-2-carboxylic acid methyl ester (CAN29682-15-3, 50 g, 0.23 mol) and m-CPBA (CAN 937-14-4, 80 g, 0.46 mol) in400 mL dry methylene chloride was heated to 60° C. for 20 h. After that,the mixture was quenched with saturated sodium sulfite solution andextracted with ethyl acetate (2×200 mL). The organic layer was washedwith brine (2×200 mL) and evaporated to dryness. The residue waspurified with by column chromatography (silica gel, 300 g, eluting with15% ethyl acetate in petroleum ether) to obtain a brown oil. The brownoil, 5-bromo-2-(methoxycarbonyl)pyridine 1-oxide (30 g, 0.13 mol) wasadded into phosphoryl trichloride (CAN 10025-87-3, 80 mL) at 0° C. over1 h, then the mixture was heated to 95° C. for 1 h. After that themixture was evaporated to dryness, the residue was dissolved in water(50 mL), extracted with ethyl acetate (3×50 mL) and the organic layerwas evaporated to dryness to obtain the product as a white solid (19 g,59%); MS (EI): m/e=249.9 [MH⁺].

b) 5-Bromo-6-cyclopropylmethoxy-pyridine-2-carboxylic acid

Sodium hydride (4.83 g, 0.12 mol) was added into cyclopropanemethanol(CAN 2516-33-8, 30 g) at 0° C. and the mixture was stirred at 0° C. for1 h. Then to the mixture was added methyl5-bromo-6-chloro-pyridine-2-carboxylic acid methyl ester (3 g, 12.75mmol). The obtained solution was heated to 90° C. for 2 h. Then themixture was evaporated to dryness, the residue was dissolved in 40 mL ofwater, and adjusted to pH=4 with hydrochloric acid (3 N), and extractedwith ethyl acetate (3×30 mL). The combined organic layer was washed withwater (2×30 mL) and brine (2×50 mL) then evaporated to dryness to obtainthe product as a white solid (2.5 g, 76.7%); MS (EI): m/e=272.0 [MH⁺].

c) 5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid

A mixture of 5-bromo-6-(cyclopropylmethoxy)-pyridine-2-carboxylic acid(1.5 g, 5.5 mmol), cyclopropylboronic acid (CAN 411235-57-9, 0.57 g, 7mmol), palladium diacetate (CAN 3375-31-3, 62 mg, 0.28 mmol),tricyclohexylphosphine (CAN 2622-14-2, 154 mg, 0.1 mmol) and potassiumphosphate (4.1 g, 19 mmol) in toluene/water (20/1 v/v, 30 mL) was heatedto 100° C. overnight. After that the mixture was evaporated to dryness,dissolved in 30 mL of water, extracted with ethyl acetate (30 mL) andthe organic layer was dropped. The water layer was adjusted to pH=3 andextracted with ethyl acetate (2×30 mL), this organic layer was washedwith water (30 mL) and brine (30 mL), dried over anhydrous sodiumsulfate then evaporated to dryness. The residue was purified by columnchromatography (silica gel, 10 g, eluting with 15% ethyl acetate inpetroleum ether) to obtain the title compound (0.96 g, 75%) as whitesolid; MS (LC/MS): 234.1 [MH⁺].

d) 5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acidtert-butyl-methyl-amide

In analogy to the procedure described in Example 47 b),5-cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid wasreacted with N,2-dimethylpropan-2-amine (CAN 94896-77-2) in the presenceof TBTU and DIEA to give the title compound as colorless oil; MS (EI):m/e=303.4 [MH⁺].

Example 45-Cyclopropyl-6-(tetrahydro-furan-2-ylmethoxy)-pyridine-2-carboxylicacid tert-butyl-methyl-amide a)5-Bromo-6-(tetrahydro-furan-2-ylmethoxy)-pyridine-2-carboxylic acid

5-Bromo-6-chloropicolinic acid (200 mg, 846 μmol; CAN 959958-25-9) andpowdered potassium hydroxide (190 mg, 3.38 mmol) were combined with DMSO(1.93 mL) to give a colorless solution which was stirred for 15 min atambient temperature before tetrahydro-2-furanmethanol (130 mg, 123 μl,1.27 mmol, CAN 97-99-4) was added, and stirring continued for 1 day atambient temperature. The reaction mixture was poured into a mixture ofice-water and 1 M NaOH, and extracted with t-butylmethyl ether (2×25 mL)and washed with ice-water/brine. The water phases were combinedacidified with ice/1 N HCl and extracted with isopropyl acetate (2×30mL). The organic layers were washed with ice-water/brine (2×30 mL),dried with Na₂SO₄ and concentrated in vacuo to give the title compound(254 mg, 99%) as light brown oil; MS (ESI): 301.8 [M−H]⁻.

b) 5-Cyclopropyl-6-(tetrahydro-furan-2-ylmethoxy)-pyridine-2-carboxylicacid

Palladium(II)acetate (1.19 mg, 5.3 μmol),butylbis(tricyclo[3.3.1.13,7]dec-1-yl)-phosphine (2.85 mg, 7.94 μmol,CAN 321921-71-5), potassium cyclopropyltrifluoroborate (39.6 mg, 267μmol) and cesium carbonate (259 mg, 794 μmol) were combined to give awhite solid. To this solid a degassed solution of5-bromo-6-(tetrahydro-furan-2-ylmethoxy)-pyridine-2-carboxylic acid (80mg, 265 μmol) in toluene (2.02 mL)/water (224 μL) was added through aseptum cap. The reaction mixture was heated to 120° C. and stirred for20 h. After cooling to ambient temperature the reaction mixture wasdiluted with water (2 mL), poured onto 20 mL ice water/brine/1 N HCl,extracted with isopropyl acetate (2×40 mL), and washed with 20 mL icewater/brine. The organic layers were dried with Na₂SO₄ and concentratedin vacuo to give a light brown oily residue which was purified bypreparative TLC (silica gel, 2.0 mm, DCM/MeOH, 49:1). The title compound(25 mg, 36%) was isolated as light yellow liquid; MS (ESI): 262.0[M−H]⁻.

c) 5-Cyclopropyl-6-(tetrahydro-furan-2-ylmethoxy)-pyridine-2-carboxylicacid tert-butyl-methyl-amide

In analogy to the procedure described in Example 47 b),5-cyclopropyl-6-(tetrahydro-furan-2-ylmethoxy)-pyridine-2-carboxylicacid was reacted with N,2-dimethylpropan-2-amine (CAN 94896-77-2) in thepresence of TBTU and DIEA to give the title compound as colorless oil;MS (EI): m/e=333.5 [MH⁺].

Example 5 5-Cyclopropyl-6-(4-fluoro-benzyl)-pyridine-2-carboxylic acidtert-butyl-methyl-amide a) 5-Bromo-6-methyl-pyridine-2-carbonitrile

NaCN (4 g, 82 mmol) was added to a solution of3-bromo-6-fluoro-2-methyl-pyridine (4 g, 21 mmol) in DMSO (100 mL) Themixture was stirred for 2 h at 100° C., poured into H₂O (100 mL) andextracted with ethyl acetate (2×100 mL). The organic layers were driedover Na₂SO₄, concentrated and purified by flash column chromatography(silica gel, 10 g, eluting with 10% ethyl acetate in petroleum ether) togive the title compound (0.6 g, 15%) as white solid; MS (EI): m/e=197.0[1\4+H]⁺.

b) 5-Cyclopropyl-6-methyl-pyridine-2-carbonitrile

5-Bromo-6-methyl-pyridine-2-carbonitrile (0.5 g, 2.5 mmol),cyclopropylboronic acid (CAN 411235-57-9, 0.36 g, 4 mmol), Pd₂(dba)₃(CAN 411235-57-9, 0.1 g, 0.2 mmol), xantphos (CAN 161265-03-8, 0.15 g,0.26 mmol) and Cs₂CO₃ (1.1 g, 3 mmol) were suspended in 1,4-dioxane (30mL) under a nitrogen atmosphere. The mixture was stirred for 12 h at110° C., filtered, concentrated under reduced pressure and purified bycolumn chromatography (silica gel, 5 g, eluting with 10% ethyl acetatein petroleum ether) to give the title compound (0.3 g, 75%) as yellowsolid; MS (EI): m/e=159.2 [M+H]⁺.

c) 5-Cyclopropyl-6-methyl-1-oxy-pyridine-2-carbonitrile

A mixture of 5-cyclopropyl-6-methyl-pyridine-2-carbonitrile (0.2 g, 1.3mmol) and m-CPBA (0.5 g, 3 mmol) in CH₂Cl₂ (10 mL) was stirred for 12hours at 60° C. After cooling to ambient temperature, the mixture wasfiltered, concentrated under reduced pressure and purified by columnchromatography (silica gel, 3 g, eluting with 50% ethyl acetate inpetroleum ether) to give the title compound (0.2 g, 91%) as yellowsolid; MS (EI): m/e=175.0 [M+H]⁺.

d) 5-Cyclopropyl-6-hydroxymethyl-pyridine-2-carbonitrile

Trifluoroacetic acid anhydride (CAN 457-25-0, 1 mL) was added to asolution of 5-cyclopropyl-6-methyl-1-oxy-pyridine-2-carbonitrile (0.2 g,1.1 mmol) in CH₂Cl₂ (10 mL). The reaction mixture was stirred for 12 hat ambient temperature and then partitioned between 6 N NaOH aq. (10 mL)and CH₂Cl₂ (10 mL). The aqueous phase was washed several times withCH₂Cl₂ and the combined organic fractions were dried over Na₂SO₄ andconcentrated under reduced pressure. The residue was purified by columnchromatography (silica gel, 3 g, eluting with 1% methanol in methylenechloride) to give the title compound (0.1 g, 50%) as yellow oil; MS(EI): m/e=175.2 [M+H]⁺.

e) 6-Bromomethyl-5-cyclopropyl-pyridine-2-carbonitrile

A solution of 5-cyclopropyl-6-hydroxymethyl-pyridine-2-carbonitrile (0.1g, 0.6 mmol), CBr₄ (0.8 g, 1.2 mmol), PPh₃ (0.3 g, 1.2 mmol) in THF (10mL) was stirred for 12 h at 40° C. The solvent was removed under reducedpressure and the crude product purified by flash column chromatography(silica gel, 3 g, eluting with 25% ethyl acetate in petroleum ether) togive the title compound (0.1 g, 74%) as yellow solid; MS (EI): m/e=236.9[M+H]⁺.

f) 5-Cyclopropyl-6-(4-fluoro-benzyl)-pyridine-2-carbonitrile

A mixture of 6-bromomethyl-5-cyclopropyl-pyridine-2-carbonitrile (0.1 g,0.4 mmol), 4-fluoro-benzylboronic acid (CAN 1765-93-1, 0.1 g, 0.7 mmol),Pd(dppf)Cl₂ (CAN 95464-05-4, 50 mg, 0.068 mmol), Cs₂CO₃ (0.2 g, 0.6mmol) in 1.4-dioxane (10 mL) was stirred for 12 h at 110° C. under anitrogen atmosphere. The mixture was filtered, concentrated and purifiedby flash column chromatography (silica gel, 3 g, eluting with 25% ethylacetate in petroleum ether) to give the title compound (80 mg, 75%) asyellow solid; MS (EI): m/e=253.2 [M+H]⁺.

g) 5-Cyclopropyl-6-(4-fluoro-benzyl)-pyridine-2-carboxylic acid

A solution of 5-cyclopropyl-6-(4-fluoro-benzyl)-pyridine-2-carbonitrile(0.08 g, 0.3 mmol) and NaOH (0.05 g, 1.2 mmol) in H₂O (10 mL) wasstirred for 2 hours at 90° C. The pH was adjusted to 3 with 1 M HCl. Themixture was extracted with ethyl acetate (3×10 mL), dried over Na₂SO₄,concentrated under reduced pressure and purified by columnchromatography to give the title compound (0.06 g, 70%) as yellow solid;MS (EI): m/e=272.1 [M+H]⁺.

h) 5-Cyclopropyl-6-(4-fluoro-benzyl)-pyridine-2-carboxylic acidtert-butyl-methyl-amide

In analogy to the procedure described in Example 47 b),5-cyclopropyl-6-(4-fluoro-benzyl)-pyridine-2-carboxylic acid was reactedwith N,2-dimethylpropan-2-amine (CAN 94896-77-2) in the presence of TBTUand DIEA to give the title compound as colorless oil; MS (EI): m/e=341.1[MH⁺].

Example 65-Cyclopropyl-6-(2-methyl-propane-1-sulfonyl)-pyridine-2-carboxylic acidtert-butyl-methyl-amide a) 5-Bromo-6-(isobutylthio)picolinic acid

5-Bromo-6-chloropicolinic acid (2 g, 8.46 mmol; CAN 959958-25-9),2-methylpropane-1-thiol (915 mg, 1.1 mL, 10.2 mmol) and cesium carbonate(6.89 g, 21.1 mmol) were suspended in DMSO (100 mL). The reactionmixture was heated to 150° C. and stirred for 1 d and was poured ontoice-water/1N HCl (100 mL). The aqueous layer was extracted with EtOAc(2×250 mL). The combined extracts were washed with ice-water/brine (100mL), dried over Na₂SO₄ and concentrated in vacuo to give the titlecompound (2.49 g, 51%) as an orange solid which was used in the nextstep without further purification. MS (EI): m/e=288.4 [M−H]⁻.

b) Methyl 5-bromo-6-(isobutylthio)picolinate

5-Bromo-6-(isobutylthio)picolinic acid (500 mg, 1.72 mmol) was dissolvedin methanol (5 mL) to give a yellow solution. Sulfuric acid (169 mg,92.3 μL, 1.72 mmol) was added. The reaction mixture was heated to 80° C.and stirred for 1 d. The reaction mixture was cooled to 0° C. and pouredonto ice-water/brine (25 mL). The aqueous layer was extracted with EtOAc(2×40 mL) and washed with ice-water/brine (20 mL). The organic layerswere combined, dried over Na₂SO₄ and concentrated in vacuo to give crudetitle compound as a yellow oil. The oil was purified by flashchromatography (silica gel, 5 g, 0% to 15% EtOAc in heptane) to give thetitle product (205 mg, 39%) as a colorless oil. MS (EI): m/e=306.3[M+H]⁺.

c) Methyl 5-bromo-6-(isobutylsulfonyl)picolinate

Methyl 5-bromo-6-(isobutylthio)picolinate (30 mg, 98.6 μmol) wasdissolved in dichloromethane (1 mL). The solution was cooled to 0° C.3-Chlorobenzoperoxoic acid (34.0 mg, 197 μmol) was added. The reactionmixture was stirred for 1 d at ambient temp., poured onto ice-water (20mL) and extracted with dichloromethane (2×30 mL). The extract was washedwith a 10% aqueous Na₂S₂O₃-solution (15 mL). The aqueous layer wasback-extracted with dichloromethane (30 mL). The combined organic layerswere washed with an aqueous 10% sodium hydrogen carbonate solution,dried over Na₂SO₄ and concentrated in vacuo to give the crude product asa white solid. Filtration through silica gel (3 g, heptane/EtOAc 1:1)provided the title compound (19 mg, 70%) as a white oil. MS (EI):m/e=338.3 [M+H]⁺.

d) 5-Cyclopropyl-6-(isobutylsulfonyl)picolinic acid

The title compound was prepared in analogy to the procedure described inExample 3 c), using methyl 5-bromo-6-(isobutylsulfonyl)picolinate asstarting material. MS (EI): m/e=284.3 [M+H]⁺.

e) 5-Cyclopropyl-6-(2-methyl-propane-1-sulfonyl)-pyridine-2-carboxylicacid tert-butyl-methyl-amide

In analogy to the procedure described in Example 47 b),5-cyclopropyl-6-(isobutylsulfonyl)picolinic acid was reacted withN,2-dimethylpropan-2-amine (CAN 94896-77-2) in the presence of TBTU andDIEA to give the title compound as white solid; MS (EI): m/e=353.5[MH⁺].

Example 76-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylicacid tert-butyl-ethyl-amide

In analogy to the procedure described in Example 47 b),6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylicacid (Example 1 b)) was reacted with N-ethyl-2-methylpropan-2-amine (CAN4432-77-3) in the presence of TBTU and DIEA to give the title compoundas colorless oil; MS (EI): m/e=368.5 [MH⁺].

Example 8Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylicacid diisopropylamide

In analogy to the procedure described in Example 47 b),6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylicacid (Example 1 b)) was reacted with (3-methyloxetan-3-yl)methanamine(CAN 153209-97-3) in the presence of TBTU and DIEA to give the titlecompound as a byproduct as colorless oil; MS (EI): m/e=368.5 [MH⁺].

Example 96-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylicacid (2-methoxy-1,1-dimethyl-ethyl)-methyl-amide

In analogy to the procedure described in Example 47 b),6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylicacid (Example 1 b)) was reacted with3-methoxy-2,2-dimethylpropan-1-amine (CAN 1177316-77-6) in the presenceof TBTU and DIEA to give the title compound as colorless oil; MS (EI):m/e=384.5 [MH⁺].

Example 10[6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridin-2-yl]-(6-oxa-1-aza-spiro[3.3]hept-1-yl)-methanone

In analogy to the procedure described in Example 47 b),6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylicacid (Example 1 b)) was reacted with 6-oxa-1-azaspiro[3.3]heptaneoxalate (CAN 1359655-43-8) in the presence of TBTU and DIEA to give thetitle compound as colorless oil; MS (EI): m/e=366.4 [MH⁺].

Example 11[6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridin-2-yl]-(2-oxa-6-aza-spiro[3.3]hept-6-yl)-methanone

In analogy to the procedure described in Example 47 b),6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylicacid (Example 1 b)) was reacted with 2-oxa-6-azaspiro[3.3]heptaneoxalate (CAN 1159599-99-1) in the presence of TBTU and DIEA to give thetitle compound as colorless oil; MS (EI): m/e=366.4 [MH⁺].

Example 126-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylicacid2-{[6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carbonyl]-methyl-amino}-2-methyl-propylester

In analogy to the procedure described in Example 47 b),6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylicacid (Example 1 b)) was reacted with 2-methyl-2-(methylamino)propan-1-ol(CAN 27646-80-6) in the presence of TBTU and DIEA to obtain the titlecompound as colorless oil; MS (EI): m/e=636.3 [MH⁺].

Example 135-Cyclopropyl-6-(2,2,2-trifluoro-1-methyl-ethoxy)-pyridine-2-carboxylicacid tert-butyl-methyl-amide a)5-Bromo-6-(1,1,1-trifluoropropan-2-yloxy)picolinic acid

5-Bromo-6-chloropicolinic acid (5 g, 21.1 mmol; CAN 959958-25-9) wasdissolved in DMSO (100 mL) to give a colorless solution. To thissolution potassium hydroxide (4.75 g, 84.6 mmol) was added. The reactionmixture turned into a white suspension which was stirred for 15 min.Then 1,1,1-trifluoropropan-2-ol (2.41 g, 1.92 mL, 21.1 mmol) was added.The mixture was stirred for 1 d at ambient temp., poured ontoice-water/1N HCl (200 mL) and extracted with EtOAc (2×400 mL). Theorganic layers were washed with ice-water/brine (200 mL), combined anddried over Na₂SO₄ and concentrated in vacuo to give the title compound(6.9 g, quant.) as orange solid. MS (EI): m/e=312.3 [M−H]⁻.

b) 5-Cyclopropyl-6-(1,1,1-trifluoropropan-2-yloxy)picolinic acid

5-Bromo-6-(1,1,1-trifluoropropan-2-yloxy)picolinic acid (2 g, 6.37mmol), potassium cyclopropyltrifluoroborate (952 mg, 6.43 mmol), cesiumcarbonate (6.22 g, 19.1 mmol) and palladium(II)acetate (28.6 mg, 127μmol) were suspended in toluene (55 mL) and water (6.11 mL) under anargon atmosphere. Butyl-1-adamantylphosphin (68.5 mg, 191 μmol) wasadded, the reaction mixture was heated to 120° C. for 1 d, poured ontoice-water/1N HCl (150 mL) and extracted with EtOAc (2×300 mL). Thecombined organic layers were washed with ice-water/brine (150 mL), driedover Na₂SO₄ and concentrated in vacuo to give the title compound (1.38g, 79%) as a yellow solid. MS (EI): m/e=276.2 [M+H]⁺.

c)5-Cyclopropyl-6-(2,2,2-trifluoro-1-methyl-ethoxy)-pyridine-2-carboxylicacid tert-butyl-methyl-amide

In analogy to the procedure described in Example 47 b),5-cyclopropyl-6-(1,1,1-trifluoropropan-2-yloxy)picolinic acid wasreacted with 2-methyl-2-(methylamino)propan-1-ol (CAN 27646-80-6) in thepresence of TBTU and DIEA to obtain the title compound as white solid;MS (EI): m/e=345.4 [MH⁺].

Example 14[6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridin-2-yl]-(4,4-dimethyl-oxazolidin-3-yl)-methanone

In analogy to the procedure described in Example 47 b),6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylicacid (Example 1 b)) was reacted with 4,4-dimethyloxazolidine (CAN51200-87-4) in the presence of TBTU and DIEA to obtain the titlecompound as white solid; MS (EI): m/e=368.5 [MH⁺].

Example 156-(Tetrahydro-furan-2-ylmethoxy)-5-trifluoromethyl-pyridine-2-carboxylicacid tert-butyl-methyl-amide a)6-(Tetrahydro-furan-2-ylmethoxy)-5-trifluoromethyl-pyridine-2-carboxylicacid

In analogy to the procedure described in Example 4 a),6-chloro-5-(trifluoromethyl)picolinic acid (CAN 855915-21-8) was reactedwith (tetrahydrofuran-2-yl)methanol (CAN 97-99-4) in the presence ofpotassium hydroxide to yield the title compound as yellow solid; MS(EI): m/e=290.0 [MH⁺].

b)6-(Tetrahydro-furan-2-ylmethoxy)-5-trifluoromethyl-pyridine-2-carboxylicacid tert-butyl-methyl-amide

In analogy to the procedure described in Example 47 b),6-((tetrahydrofuran-2-yl)methoxy)-5-(trifluoromethyl)picolinic acid wasreacted with N,2-dimethylpropan-2-amine (CAN 94896-77-2) in the presenceof TBTU and DIEA to give the title compound as colorless oil; MS (EI):m/e=361.5 [MH⁺].

Example 166-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylicacid methyl-(1-trifluoromethyl-cyclopropyl)-amide a)6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylicacid (1-trifluoromethyl-cyclopropyl)-amide

The title compound was synthesized in analogy to the procedure describedin Example 47 b), using6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylicacid (Example 1 b)) and 1-(trifluoromethyl)cyclopropanamine (CAN112738-68-8) as starting materials. MS (EI): m/e=392.4 [M+H]⁺.

b)6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylicacid methyl-(1-trifluoromethyl-cyclopropyl)-amide

A solution of6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylicacid (1-trifluoromethyl-cyclopropyl)-amide (20 mg, 51.1 μmol) and sodiumhydride (3.3 mg, 76.7 μmol) in DMF (0.2 mL) was stirred for 15 min. atambient temperature. Iodomethane (14.5 mg, 6.38 μL, 102 μmol) was addedand stirring was continued for 1 h. The reaction mixture was poured ontoice/sat. aqueous NaHCO₃ solution (15 mL) and extracted with EtOAc (2×25mL). The combined extracts were washed with ice water/brine (2×20 mL),dried over Na₂SO₄ and brought to dryness. The crude brown oil waspurified by preparative TLC (silica gel, 1 mm, heptan/EtOAc 4:1, elutionwith EtOAc) to give the title compound (13 mg, 63%) as colorless oil; MS(EI): m/e=406.4 [MH]⁺.

Example 17[6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridin-2-yl]-(3,3-dimethyl-morpholin-4-yl)-methanone

In analogy to the procedure described in Example 47 b),6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylicacid (Example 1 b)) was reacted with 3,3-dimethylmorpholine (CAN59229-63-9) in the presence of TBTU and DIEA to obtain the titlecompound as colorless oil; MS (EI): m/e=382.4 [MH⁺].

Example 18[6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridin-2-yl]-(2,2-dimethyl-pyrrolidin-1-yl)-methanone

In analogy to the procedure described in Example 47 b),6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylicacid (Example 1 b)) was reacted with 2,2-dimethylpyrrolidine (CAN35018-15-6) in the presence of TBTU and DIEA to obtain the titlecompound as colorless oil; MS (EI): m/e=366.4 [MH⁺].

Example 196-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylicacid (2-hydroxy-1,1-dimethyl-ethyl)-(2-methoxy-ethyl)-amide

In analogy to the procedure described in Example 47 b),6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylicacid (Example 1 b)) was reacted with2-(2-methoxyethylamino)-2-methylpropan-1-ol (CAN 1156380-97-0) in thepresence of TBTU and DIEA to obtain the title compound as colorless oil;MS (EI): m/e=414.4 [MH⁺].

Example 206-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylicacid tert-butyl-(2-methoxy-ethyl)-amide

In analogy to the procedure described in Example 47 b),6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylicacid (Example 1 b)) was reacted withN-(2-methoxyethyl)-2-methylpropan-2-amine (CAN 22687-22-5) in thepresence of TBTU and DIEA to obtain the title compound as colorless oil;MS (EI): m/e=398.4 [MH⁺].

Example 216-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylicacid ethyl-(1-trifluoromethyl-cyclopropyl)-amide

A solution of6-(cyclopropylmethoxy)-5-(3,3-difluoroazetidin-1-yl)-N-(1-(trifluoromethyl)cyclopropyl)picolinamide(Example 16 a), 15 mg, 38 μmol) and sodium 2-methylbutan-2-olate (5 mg,46 μmol) in DMF (150 μL) was stirred for 15 minutes at ambienttemperature. Iodoethane (9 mg, 7 μL, 58 μmol) was added and stirring wascontinued for 1 h. The reaction mixture was poured onto ice/sat. aqueousNaHCO₃ solution (15 mL) and extracted with EtOAc (2×25 mL). The combinedextracts were washed with ice/brine (2×20 mL), dried over Na₂SO₄ andbrought to dryness. The crude product was purified by preparative TLC(silica gel, 1 mm, heptan/EtOAc 2:1, elution with EtOAc) to give thetitle compound (12 mg, 75%) as colorless oil; MS (EI): m/e=420.2 [MH]⁺.

Example 226-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylicacid benzyl-(1-trifluoromethyl-cyclopropyl)-amide

In analogy to the procedure described in Example 16 b),6-(cyclopropylmethoxy)-5-(3,3-difluoroazetidin-1-yl)-N-(1-(trifluoromethyl)cyclopropyl)picolinamide(Example 16 a) was reacted with (chloromethyl)benzene (CAN 27987-13-9)in the presence of sodium hydride to give the title compound ascolorless oil; MS (EI): m/e=482.4 [MH]⁺.

Example 23{tert-Butyl-[6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carbonyl]-amino}-aceticacid ethyl ester

In analogy to the procedure described in Example 47 b),6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylicacid (Example 1 b)) was reacted with ethyl 2-(tert-butylamino)acetate(CAN 37885-76-0) in the presence of TBTU and DIEA to obtain the titlecompound as colorless oil; MS (EI): m/e=426.5 [MH⁺].

Example 24{tert-Butyl-[6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carbonyl]-amino}-aceticacid

A solution of2-(N-tert-butyl-6-(cyclopropylmethoxy)-5-(3,3-difluoroazetidin-1-yl)picolinamido)acetate(Example 23, 58 mg, 136 μmol) in a mixture of 1N aqueous NaOH solution(164 μL, 164 μmol), THF (0.5 mL), MeOH (0.2 mL) and water (0.05 mL) wasstirred at ambient temperature for 24 h and evaporated to dryness. Theresidue was partitioned between ice water/0.1N aqueous HCl solution (25mL) and EtOAc (25 mL). The aqueous layer was extracted one more timewith EtOAc (25 mL). The combined extracts were washed with ice/brine (25mL), dried over Na₂SO₄ and brought to dryness to give the title compound(51 mg, 128 μmol, 94%) as light yellow solid; MS (EI): m/e=398.4 [MH⁺].

Example 256-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylicacid benzyl-tert-butyl-amide

In analogy to the procedure described in Example 47 b),6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylicacid (Example 1 b)) was reacted with N-benzyl-2-methylpropan-2-amine(CAN 3378-72-1) in the presence of TBTU and DIEA to obtain the titlecompound as colorless solid; MS (EI): m/e=430.5 [MH⁺].

Example 266-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylicacid tert-butyl-methylcarbamoylmethyl-amide

In analogy to the procedure described in Example 47 b),{tert-butyl-[6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carbonyl]-amino}-aceticacid (Example 24) was reacted with a 2 M solution of methanamine (CAN74-89-5) in MeOH in the presence of TBTU and DIEA to obtain the titlecompound as colorless oil; MS (EI): m/e=411.5 [MH⁺].

Example 276-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylicacid tert-butyl-dimethylcarbamoylmethyl-amide

In analogy to the procedure described in Example 47 b),{tert-butyl-[6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carbonyl]-amino}-aceticacid (Example 24) was reacted with dimethylamine hydrochloride (CAN506-59-2) in the presence of TBTU and DIEA to obtain the title compoundas colorless oil; MS (EI): m/e=425.5 [MH⁺].

Example 284-[6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carbonyl]-3,3-dimethyl-piperazin-2-one

In analogy to the procedure described in Example 47 b),6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylicacid (Example 1 b)) was reacted with 3,3-dimethylpiperazin-2-onehydrochloride (CAN 1104383-07-4) in the presence of TBTU and DIEA toobtain the title compound as white solid; MS (EI): m/e=395.4 [MH⁺].

Example 294-[6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carbonyl]-3,3-diethyl-piperazin-2-one

In analogy to the procedure described in Example 47 b),6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylicacid (Example 1 b)) was reacted with 3,3-dimethylpiperazin-2-onehydrochloride (CAN 907973-05-1) in the presence of TBTU and DIEA toobtain the title compound as colorless solid; MS (EI): m/e=423.4 [MH⁺].

Example 30[5-Cyclopropyl-6-(2-methyl-propane-1-sulfonyl)-pyridin-2-yl]-(2,2-dimethyl-pyrrolidin-1-yl)-methanone

In analogy to the procedure described in Example 47 b),5-cyclopropyl-6-(isobutylsulfonyl)picolinic acid (Example 6 d)) wasreacted with 2,2-dimethylpyrrolidine (CAN 35018-15-6) in the presence ofTBTU and DIEA to obtain the title compound as colorless solid; MS (EI):m/e=365.5 [MH⁺].

Example 31[5-Cyclopropyl-6-(2-methyl-propane-1-sulfonyl)-pyridin-2-yl]-(4,4-dimethyl-oxazolidin-3-yl)-methanone

In analogy to the procedure described in Example 47 b),5-cyclopropyl-6-(isobutylsulfonyl)picolinic acid (Example 6 d)) wasreacted with 4,4-dimethyloxazolidine (CAN 51200-87-4) in the presence ofTBTU and DIEA to obtain the title compound as colorless solid; MS (EI):m/e=367.4 [MH⁺].

Example 326-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylicacid[(S)-2-cyclopropyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethyl]-methyl-amidea) (S)-tert-Butyl 1-amino-3-cyclopropyl-1-oxopropan-2-ylcarbamate

A mixture of (S)-2-(tert-butoxycarbonylamino)-3-cyclopropylpropanoicacid (CAN 89483-06-7, 10 g, 44 mmol), di-tert-butyl dicarbonate(CAN:24424-99-5, 14.28 g, 66 mmol) and pyridine (2.4 mL) in acetonitrile(200 mL) was stirred at room temperature for 20 min. Ammonia (10 mL) wasadded dropwise for 20 min. The resulting reaction mixture was stirredfor 4 h. During removal of most of the solvent under reduced pressurethe product precipitated and the solid was filtered off and washed withacetonitrile (20 mL). The solid was dried under reduced pressure to givethe title compound (7.73 g, 78%) as white solid; MS (EI): m/e 251.2[M+Na]⁺.

b) (S)-tert-Butyl 1-cyano-2-cyclopropylethylcarbamate

To a solution of (S)-tert-butyl1-amino-3-cyclopropyl-1-oxopropan-2-ylcarbamate (3.7 g, 16 mmol) andtriethylamine (6.55 g, 65 mmol) in methylene chloride (50 mL) was addedtrifluoroacetic acid anhydride (6.81 g, 32 mmol) dropwise at 0° C. Theresulting mixture was allowed to warm to room temperature and stirredfor 4 h. The mixture was washed with water (150 mL), citric acid (150mL, 5 M) and brine (150 mL). The organic phase was dried over anhydroussodium sulfate and concentrated to give product (3.31 g, 97%) as ayellow solid; MS (EI): m/e 233.1 [M+Na]⁺.

c) (S,Z)-tert-Butyl1-amino-3-cyclopropyl-1-(hydroxyimino)propan-2-ylcarbamate

Potassium carbonate (2.18 g, 16 mmol) was dissolved in water (8 mL) andhydroxylamine hydrochloride (1.1 g, 16 mmol) was added. A solution of(S)-tert-butyl 1-cyano-2-cyclopropylethylcarbamate (3.31 g, 16 mmol) inethanol (24 mL) was added thereto and the resulting reaction mixture wasstirred for 72 h. After evaporation of solvents, the residue wasdissolved with ethyl acetate (20 mL) and then filtered. The filtrate wasconcentrated to yield crude product as yellow solid (3.61 g, 94%); MS(EI): m/e 244.2 [M+H]⁺.

d) (S)-tert-Butyl2-cyclopropyl-1-(5-methyl-1,2,4-oxadiazol-3-yl)ethylcarbamate

To a solution of acetic acid (0.224 g, 4 mmol) in DMF (5 mL) was addedN,N′-carbonyldiimidazole (0.6 g, 4 mmol) and the mixture was stirred for0.5 h at room temperature. (S,Z)-tert-butyl1-amino-3-cyclopropyl-1-(hydroxyimino)propan-2-ylcarbamate (0.84 g, 3mmol) was added and the mixture was heated to 120° C. and stirred for 4h. After evaporation of solvents, the residue was purified by columnchromatography (silica gel, 20 g, eluting with 10% ethyl acetate inpetroleum ether) to give the title compound (0.5 g; 54%) as yellowsolid; MS (EI): m/e 290.1 [M+Na]⁺.

e) (S)-2-Cyclopropyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethylamine

A solution of (S)-tert-butyl2-cyclopropyl-1-(5-methyl-1,2,4-oxadiazol-3-yl)ethylcarbamate (0.5 g, 2mmol) in sat. hydrochloric acid (10 mL) was stirred at room temperaturefor 1 h. Then water (20 mL) was added. The water phase was washed withethyl acetate (2×20 mL) and adjusted with 2 M sodium hydroxide solutionto pH=9-10. It was then extracted with ethyl acetate (2×20 mL). Theorganic layer was washed with brine (20 mL), dried over anhydrous sodiumsulfate and concentrated to give crude product as a white solid (0.25 g,80%); MS (EI): m/e 168.2 [M+H]⁺.

f)6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylicacid [(S)-2-cyclopropyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethyl]-amide

In analogy to the procedure described in Example 47 b),6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylicacid (Example 1 b)) was reacted with(S)-2-cyclopropyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethylamine in thepresence of TBTU and DIEA to obtain the title compound; MS (EI):m/e=434.2 [MH⁺].

g)6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylicacid[(S)-2-cyclopropyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethyl]-methyl-amide

In analogy to the procure described in Example 16 b),6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylicacid [(S)-2-cyclopropyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethyl]-amidewas reacted with methyl iodide (CAN 74-88-4) in the presence of sodiumhydride to give the title compound as colorless oil; MS (EI): m/e=448.2[MH]⁺.

Example 335-Cyclopropyl-6-(tetrahydro-pyran-4-ylmethoxy)-pyridine-2-carboxylicacid [cyclopropyl-(5-methyl-[1,2,4]oxadiazol-3-yl)-methyl]-methyl-amidea) 5-Cyclopropyl-6-(tetrahydro-pyran-4-ylmethoxy)-pyridine-2-carboxylicacid [cyclopropyl-(5-methyl-[1,2,4]oxadiazol-3-yl)-methyl]-amide

In analogy to the procedure described in Example 47 b),5-cyclopropyl-6-(tetrahydro-pyran-4-ylmethoxy)-pyridine-2-carboxylicacid (which can e.g. be prepared in a similar manner than5-cyclopropyl-6-(tetrahydro-furan-2-ylmethoxy)-pyridine-2-carboxylicacid (Example 4 b)) was reacted withcyclopropyl-(5-methyl-[1,2,4]oxadiazol-3-yl)-methylamine (which can e.g.be prepared in a similar manner than(S)-2-cyclopropyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethylamine (Example32 e)) in the presence of TBTU and DIEA to obtain the title compound ascolorless oil; MS (EI): m/e=413.1 [MH⁺].

b) 5-Cyclopropyl-6-(tetrahydro-pyran-4-ylmethoxy)-pyridine-2-carboxylicacid [cyclopropyl-(5-methyl-[1,2,4]oxadiazol-3-yl)-methyl]-methyl-amide

In analogy to the procure described in Example 16 b),5-cyclopropyl-6-(tetrahydro-pyran-4-ylmethoxy)-pyridine-2-carboxylicacid [cyclopropyl-(5-methyl-[1,2,4]oxadiazol-3-yl)-methyl]-amide wasreacted with methyl iodide (CAN 74-88-4) in the presence of sodiumhydride to give the title compound as colorless oil; MS (EI): m/e=427.2[MH]⁺.

Example 34(+)-6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylicacid methyl-(3-methyl-1-pyridazin-3-yl-butyl)-amide a)3-Methyl-1-(pyridazin-3-yl)butan-1-amine

A suspension of 3-methyl-1-(pyridazin-3-yl)butan-1-one (0.85 g, 5.2mmol; CAN 138835-88-8), sodium cyanoborohydride (1.2 g, 19.2 mmol) andammonium acetate (1.28 g, 16.6 mmol) in methanol (11.1 mL) was heated at70° C. for 12 h. The solvent was removed under reduced pressure and theresidual oil was partitioned between EtOAc and 1 M aqueous HCl solution.The aqueous layer was basified with 10% aqueous NaOH solution andextracted with EtOAc. The combined extracts were washed with brine anddried over Na₂SO₄. Filtration and evaporation provided the titlecompound (233 mg, 27%) as brown oil which was sufficiently pure to beused in the next reaction step. MS (EI): m/e=166.2 [M+H]⁺.

b)(+)-6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylicacid (3-methyl-1-pyridazin-3-yl-butyl)-amide

The title compound was synthesized in analogy to Example 47 b), using6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylicacid (Example 1 b)) and 3-methyl-1-(pyridazin-3-yl)butan-1-amine asstarting materials. The product was isolated by chiral chromatography onReprosil Chiral NR using a mixture of heptane, ethanol and 2-propanol aseluent. The (+)-enantiomer was isolated. MS (EI): m/e=432.5 [MH⁺].

c)(+)-6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylicacid methyl-(3-methyl-1-pyridazin-3-yl-butyl)-amide

In analogy to the procure described in Example 16 b),(+)-6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylicacid (3-methyl-1-pyridazin-3-yl-butyl)-amide was reacted with methyliodide (CAN 74-88-4) in the presence of sodium hydride to give the titlecompound as colorless oil; MS (EI): m/e=446.2 [MH]⁺.

Example 356-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylicacid tert-butyl-carbamoylmethyl-amide

In analogy to the procedure described in Example 47 b),6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylicacid (Example 1 b)) was reacted with 2-(tert-butylamino)acetamide(207925-15-3) in the presence of TBTU and DIEA to obtain the titlecompound as white solid; MS (EI): m/e=397.5 [MH⁺].

Example 366-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylicacid tert-butyl-(5-methyl-[1,3,4]oxadiazol-2-ylmethyl)-amide a)2-Methyl-N-((5-methyl-1,3,4-oxadiazol-2-yl)methyl)propan-2-amine

A suspension of 2-methylpropan-2-amine (75-64-9, 141 mg, 202 μL, 1.92mmol) and 2-(chloromethyl)-5-methyl-1,3,4-oxadiazole (3914-42-9, 50 mg,377 μmol) in DMF (200 μL) was stirred at ambient temperature for 16 h.The mixture was poured onto ice-water (20 mL) and extracted with CH₂Cl₂(2×30 mL). The combined extracts were washed with ice-water (20 mL),dried over Na₂SO₄ and concentrated in vacuo to give a yellow oil. Thecrude product was purified by preparative TLC (silica gel 1 mm,EtOAc/diethyl amine 95:5, elution with DCM/EtOAc 1:1) to give the titlecompound (45 mg, 71%) as yellow oil; MS (EI): m/e=170.2 [MH⁺].

b)6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylicacid tert-butyl-(5-methyl-[1,3,4]oxadiazol-2-ylmethyl)-amide

In analogy to the procedure described in Example 47 b),6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylicacid (Example 1 b)) was reacted with2-methyl-N-((5-methyl-1,3,4-oxadiazol-2-yl)methyl)propan-2-amine in thepresence of TBTU and DIEA to obtain the title compound as yellow solid;MS (EI): m/e=436.4 [MH⁺].

Example 37[6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridin-2-yl]-(3-hydroxy-3-methyl-pyrrolidin-1-yl)-methanone

In analogy to the procedure described in Example 47 b),6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylicacid (Example 1 b)) was reacted with 3-methylpyrrolidin-3-ol(125032-87-3) in the presence of TBTU and DIEA to obtain the titlecompound as yellow solid; MS (EI): m/e=368.5 [MH⁺].

Example 38 5-Chloro-4-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylicacid (2,2-dimethyl-1-thiazol-2-yl-propyl)-amide

In analogy to the procedure described in Example 47 b),6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylicacid (Example 1 b)) was reacted with 2-oxa-5-azaspiro[3.4]octane oxalate(90207-55-9) in the presence of TBTU and DIEA to obtain the titlecompound as yellow solid; MS (EI): m/e=380.3 [MH⁺].

Example 396-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylicacid ethyl-(2-methoxy-ethyl)-amide

In analogy to the procedure described in Example 47 b),6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylicacid (Example 1 b)) was reacted with N-ethyl-2-methoxyethanamine(34322-82-2) in the presence of TBTU and DIEA to obtain the titlecompound as colorless oil; MS (EI): m/e=370.6 [MH⁺].

Example 406-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylicacid tert-butyl-(1-methyl-1H-tetrazol-5-ylmethyl)-amide a)2-Methyl-N-((1-methyl-1H-tetrazol-5-yl)methyl)propan-2-aminehydrochloride

A mixture of 2-methylpropan-2-amine (75-64-9, 281 mg, 404 μL, 3.85 mmol)and 5-(chloromethyl)-1-methyl-1H-tetrazole (57235-84-4, 100 mg, 754μmol) was stirred at ambient temperature for 16 h and concentrated invacuo to give the title compound (112 mg, 72%) as yellow solid; MS (EI):m/e=169 [M⁺].

b)6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylicacid tert-butyl-(1-methyl-1H-tetrazol-5-ylmethyl)-amide

In analogy to the procedure described in Example 47 b),6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylicacid (Example 1 b)) was reacted with2-methyl-N-((1-methyl-1H-tetrazol-5-yl)methyl)propan-2-aminehydrochloride in the presence of TBTU and DIEA to obtain the titlecompound as yellow solid; MS (EI): m/e=436.5 [MH⁺].

Example 41N-{1-[6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carbonyl]-pyrrolidin-3-yl}-acetamide

In analogy to the procedure described in Example 47 b),6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylicacid (Example 1 b)) was reacted with N-(pyrrolidin-3-yl)acetamide(79286-74-1) in the presence of TBTU and DIEA to obtain the titlecompound as colorless oil; MS (EI): m/e=395.5 [MH⁺].

Example 42[5-Cyclopropyl-6-(4-fluoro-benzyl)-pyridin-2-yl]-(4,4-dimethyl-piperidin-1-yl)-methanone

In analogy to the procedure described in Example 47 b),5-cyclopropyl-6-(4-fluoro-benzyl)-pyridine-2-carboxylic acid (Example 5g)) was reacted with 4,4-dimethyl-piperidine (4045-30-1) in the presenceof TBTU and DIEA to obtain the title compound as colorless oil; MS (EI):m/e=367.5 [MH⁺].

Example 43[5-Cyclopropyl-6-(tetrahydro-furan-2-ylmethoxy)-pyridin-2-yl]-(4,4-dimethyl-piperidin-1-yl)-methanone

In analogy to the procedure described in Example 47 b),5-cyclopropyl-6-(tetrahydro-furan-2-ylmethoxy)-pyridine-2-carboxylicacid (Example 4 b)) was reacted with 4,4-dimethyl-piperidine (4045-30-1)in the presence of TBTU and DIEA to obtain the title compound ascolorless oil; MS (EI): m/e=359.6 [MH⁺].

Example 44[5-Cyclopropyl-6-(4-fluoro-benzyl)-pyridin-2-yl]-(4,4-dimethyl-oxazolidin-3-yl)-methanone

In analogy to the procedure described in Example 47 b),5-cyclopropyl-6-(4-fluoro-benzyl)-pyridine-2-carboxylic acid (Example 5g)) was reacted with 4,4-dimethyloxazolidine (CAN 51200-87-4) in thepresence of TBTU and DIEA to obtain the title compound as colorless oil;MS (EI): m/e=355.5 [MH⁺].

Example 45[6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridin-2-yl]-((1S,5R)-1,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct-6-yl)-methanone

In analogy to the procedure described in Example 47 b),6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylicacid (Example 1 b)) was reacted with(1S,5R)-1,3,3-trimethyl-6-azabicyclo[3.2.1]octane hydrochloride(380228-03-5) in the presence of TBTU and DIEA to obtain the titlecompound as colorless oil; MS (EI): m/e=420.2 [MH⁺].

Example 46[6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridin-2-yl]-((R)-2-methoxymethyl-pyrrolidin-1-yl)-methanone

In analogy to the procedure described in Example 47 b),6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylicacid (Example 1 b)) was reacted with (R)-2-(methoxymethyl)pyrrolidine(84025-81-0) in the presence of TBTU and DIEA to obtain the titlecompound as colorless oil; MS (EI): m/e=382.5 [MH⁺].

Example 47(6-Chloro-5-cyclopropylmethoxy-pyridin-2-yl)-(2,2-dimethyl-pyrrolidin-1-yl)-methanonea) Mixture of6-cyclopropylmethoxy-5-trifluoromethoxy-pyridine-2-carboxylic acid and6-chloro-5-cyclopropylmethoxy-pyridine-2-carboxylic acid

To a solution of 6-chloro-5-trifluoromethoxy-pyridine-2-carboxylic acid(CAN 1221171-90-9, 1.0 g, 4.14 mmol) in DMSO (16 mL) was added potassiumhydroxide (0.93 g, 16.6 mmol) and the reaction mixture was stirred atroom temperature for 15 minutes. To this suspension was addedcyclopropylmethanol (335 μL, 4.14 mmol) and the mixture was stirred atambient temperature for 16 hours. More cyclopropylmethanol (335 μL, 4.14mmol) was added and stirring continued for 4 hours at 50° C. The mixturewas cooled, added to 2 N sodium hydroxide solution (50 mL) with coolingand partitioned between TBME and 1 N sodium hydroxide solution. Theorganic phase was discarded; the water phases were pooled, acidifiedwith 2 N hydrochloric acid and extracted with TBME. Organic phases werepooled, dried with Na₂SO₄, filtered and concentrated in vacuo. The crudematerial (1.05 g) of a light brown solid was used without and containeda mixture of6-cyclopropylmethoxy-5-trifluoromethoxy-pyridine-2-carboxylic acid and6-chloro-5-cyclopropylmethoxy-pyridine-2-carboxylic acid (˜7/3 by NMR);LC-MS (UV peak area, ESI) 48.8%, 228.0425 [MH⁺], 51.2%, 278.0628 [MH⁺].

b)(6-Chloro-5-cyclopropylmethoxy-pyridin-2-yl)-(2,2-dimethyl-pyrrolidin-1-yl)-methanone

The mixture of6-cyclopropylmethoxy-5-trifluoromethoxy-pyridine-2-carboxylic acid and6-chloro-5-cyclopropylmethoxy-pyridine-2-carboxylic acid (Example 47 a,50 mg, 180 μmol) was dissolved in DMF (2 mL). TBTU (63.7 mg, 198 μmol),DIEA (154 μl, 902 μmol) and 2,2-dimethylpyrrolidine (CAN 35018-15-6, 24μl, 198 μmol) were added and the reaction mixture was stirred at roomtemperature for 16 hours. Ethyl acetate (3 mL) and 1 N sodium hydroxidesolution (2 mL) were added; the mixture was dried by passage throughChemElut® and concentrated in vacuo. The crude material was purified byflash chromatography (silica gel, ethyl acetate/n-heptane gradient) togive the title compound (17 mg, 31%) as off-white wax; LC-MS (UV peakarea, ESI) 97%, 309.1367 [MH⁺].

Example 48(6-Cyclopropylmethoxy-5-trifluoromethoxy-pyridin-2-yl)-(4,4-dimethyl-oxazolidin-3-yl)-methanone

The title compound was synthesized in analogy to Example 47 b, using themixture of 6-cyclopropylmethoxy-5-trifluoromethoxy-pyridine-2-carboxylicacid and 6-chloro-5-cyclopropylmethoxy-pyridine-2-carboxylic acid(Example 47 a, 50 mg, 180 μmol) and 4,4-dimethyl-oxazolidine (CAN51200-87-4; 28.4 μl (75%), 198 μmol) as starting materials and isolated(24 mg, 37%) as colorless oil; LC-MS (UV peak area, ESI) 100%, 361.1370[MH⁺].

Example 49(6-Chloro-5-cyclopropylmethoxy-pyridin-2-yl)-(4,4-dimethyl-oxazolidin-3-yl)-methanone

The title compound was synthesized in analogy to Example 47 b, using themixture of 6-cyclopropylmethoxy-5-trifluoromethoxy-pyridine-2-carboxylicacid and 6-chloro-5-cyclopropylmethoxy-pyridine-2-carboxylic acid(Example 47 a, 50 mg, 180 μmol) and 4,4-dimethyl-oxazolidine (CAN51200-87-4; 28.4 μl (75%), 198 μmol) as starting materials and isolated(13 mg, 23%) as colorless oil; LC-MS (UV peak area, ESI) 100%, 311.1158[MH⁺].

Example 506-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylicacid (1-acetyl-piperidin-4-yl)-cyclopropyl-amide

The title compound was synthesized in analogy to Example 47 b), using6-(cyclopropylmethoxy)-5-(3,3-difluoroazetidin-1-yl)picolinic acid and1-(4-(cyclopropylamino)piperidin-1-yl)ethanone (CAS 387358-46-5) asstarting materials and isolated as colorless oil. MS (EI): m/e=449.6[MH⁺].

Example 516-(Cyclopropylmethoxy)-5-(3,3-difluoroazetidin-1-yl)-N-formyl-N-methylpyridine-2-carboxamidea)6-(Cyclopropylmethoxy)-5-(3,3-difluoroazetidin-1-yl)-N-((3-(trifluoromethyl)-1,2,4-oxadiazol-5-yl)methyl)picolinamide

In analogy to the procedure described in Example 47 b),6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylicacid (Example 1 b) was reacted withC-(3-trifluoromethyl-[1,2,4]oxadiazol-5-yl)-methyl amine hydrochloride(CAS 944905-93-5) in the presence of TBTU and DIEA to give the titlecompound as white solid; MS (EI): m/e=434.5 [MH⁺].

b)6-(Cyclopropylmethoxy)-5-(3,3-difluoroazetidin-1-yl)-N-formyl-N-methylpyridine-2-carboxamide

The title compound was synthesized in analogy to the procedure describedin Example 47 b), using6-(cyclopropylmethoxy)-5-(3,3-difluoroazetidin-1-yl)-N-((3-(trifluoromethyl)-1,2,4-oxadiazol-5-yl)methyl)picolinamideas starting material. MS (EI): m/e=326.1 [M+H]⁺.

Example 526-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylicacid methyl-phenyl-amide

The title compound was synthesized in analogy to Example 47b), using6-(cyclopropylmethoxy)-5-(3,3-difluoroazetidin-1-yl)picolinic acid(Example 1 b) and N-methylaniline 2,2,2-trifluoroacetate (CAS29885-95-8) as starting materials and isolated as colorless oil. MS(EI): m/e=374.5 [MH⁺].

Example 53[6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridin-2-yl]-((S)-4,4-difluoro-2-hydroxymethyl-pyrrolidin-1-yl)-methanone

The title compound was synthesized in analogy to Example 47b), using6-(cyclopropylmethoxy)-5-(3,3-difluoroazetidin-1-yl)picolinic acid(Example 1 b) and (S)-(4,4-difluoropyrrolidin-2-yl)methanolhydrochloride (CAS 623583-10-8) as starting materials and isolated ascolorless oil. MS (EI): m/e=404.5 [MH⁺].

Example 546-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylicacid (1,4-dimethyl-1H-pyrazol-3-yl)-methyl-amide

The title compound was synthesized in analogy to Example 47b), using6-(cyclopropylmethoxy)-5-(3,3-difluoroazetidin-1-yl)picolinic acid(Example 1 b) and N,1,4-trimethyl-1H-pyrazol-3-amine (which can beprepared from 3-formylamino-1-methyl-1H-pyrazole-4-carboxylic acid ethylester CAN 114936-04-8 via reduction with lithium aluminum hydride indiethyl ether at ambient temperature) as starting materials and isolatedas colorless oil. MS (EI): m/e=392.5 [MH⁺].

Example 55[6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridin-2-yl]-(2,2-dimethyl-morpholin-4-yl)-methanone

The title compound was synthesized in analogy to Example 47b), using6-(cyclopropylmethoxy)-5-(3,3-difluoroazetidin-1-yl)picolinic acid(Example 1 b) and 2,2-dimethylmorpholine (CAS 147688-58-2) as startingmaterials and isolated as colorless oil. MS (EI): m/e=382.5 [MH⁺].

Example 56(R)-2-tert-Butyl-1-[6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carbonyl]-3-methyl-imidazolidin-4-one

The title compound was synthesized in analogy to Example 47b), using6-(cyclopropylmethoxy)-5-(3,3-difluoroazetidin-1-yl)picolinic acid(Example 1 b) and N-methylaniline 2,2,2-trifluoroacetate (CAS101143-57-1) as starting materials and isolated as colorless oil. MS(EI): m/e=423.5 [MH⁺].

Example 57(4-Aza-spiro[2.4]hept-4-yl)-[6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridin-2-yl]-methanone

In analogy to the procedure described in Example 47 b),6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylicacid (Example 1 b)) was reacted with 4-azaspiro[2.4]heptane (95442-76-5)in the presence of TBTU and DIEA to obtain the title compound ascolorless oil; MS (EI): m/e=364.5 [MH⁺].

Example 583-{1-[6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carbonyl]-piperidin-4-yl}-5,5-dimethyl-pyrrolidin-2-one

In analogy to the procedure described in Example 47 b),6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylicacid (Example 1 b)) was reacted with5,5-dimethyl-3-(piperidin-4-yl)pyrrolidin-2-one hydrochloride in thepresence of TBTU and DIEA to obtain the title compound as colorless oil;MS (EI): m/e=463.6 [MH⁺].

Example 59(1S,4R)-2-Aza-bicyclo[2.2.1]hept-2-yl-[6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridin-2-yl]-methanone

In analogy to the procedure described in Example 47 b),6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylicacid (Example 1 b)) was reacted with (1S,4R)-2-azabicyclo[2.2.1]heptanehydrochloride (175275-72-6) in the presence of TBTU and DIEA to obtainthe title compound as colorless oil; MS (EI): m/e=364.5 [MH⁺].

Example 60(S)-1-[6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carbonyl]-4,4-difluoro-pyrrolidine-2-carboxylicacid amide

In analogy to the procedure described in Example 47 b),6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylicacid (Example 1 b)) was reacted with(S)-4,4-difluoropyrrolidine-2-carboxamide hydrochloride (426844-51-1) inthe presence of TBTU and DIEA to obtain the title compound as colorlessoil; MS (EI): m/e=417.5 [MH⁺].

Example 61[6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridin-2-yl]-(4-hydroxy-4-methyl-piperidin-1-yl)-methanone

In analogy to the procedure described in Example 47 b),6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylicacid (Example 1 b)) was reacted with 4-methylpiperidin-4-olhydrochloride (586375-35-1) in the presence of TBTU and DIEA to obtainthe title compound as colorless oil; MS (EI): m/e=382.6 [MH⁺].

Example 62[6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridin-2-yl]-(1S,4S)-2-thia-5-aza-bicyclo[2.2.1]hept-5-yl-methanone

In analogy to the procedure described in Example 47 b),6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylicacid (Example 1 b)) was reacted with(1S,4S)-2-thia-5-azabicyclo[2.2.1]heptane hydrochloride (125136-43-8) inthe presence of TBTU and DIEA to obtain the title compound as colorlessoil; MS (EI): m/e=382.5 [MH⁺].

Example 63((1S,4S)-5-Benzyl-2,5-diaza-bicyclo[2.2.1]hept-2-yl)-[6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridin-2-yl]-methanone

In analogy to the procedure described in Example 47 b),6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylicacid (Example 1 b)) was reacted with(1S,4S)-2-benzyl-2,5-diazabicyclo[2.2.1]heptane dihydrobromide(116258-17-4) in the presence of TBTU and DIEA to obtain the titlecompound as colorless oil; MS (EI): m/e=455.7 [MH⁺].

Example 64[6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridin-2-yl]-(2-methyl-3-phenyl-piperidin-1-yl)-methanone

In analogy to the procedure described in Example 47 b),6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylicacid (Example 1 b)) was reacted with 2-methyl-3-phenylpiperidine(70769-67-4) in the presence of TBTU and DIEA to obtain the titlecompound as colorless oil; MS (EI): m/e=442.5 [MH⁺].

Example 65[6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridin-2-yl]-(1S,4S)-2-oxa-5-aza-bicyclo[2.2.1]hept-5-yl-methanone

In analogy to the procedure described in Example 47 b),6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylicacid (Example 1 b)) was reacted with(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptane hydrochloride (31560-06-2) inthe presence of TBTU and DIEA to obtain the title compound as colorlessoil; MS (EI): m/e=366.5 [MH⁺].

Example 66[6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridin-2-yl]-(4-hydroxy-2,2-dimethyl-piperidin-1-yl)-methanone

In analogy to the procedure described in Example 47 b),6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylicacid (Example 1 b)) was reacted with 2,2-dimethylpiperidin-4-ol(937681-12-4) in the presence of TBTU and DIEA to obtain the titlecompound as colorless oil; MS (EI): m/e=396.6 [MH⁺].

Example 671-[6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carbonyl]-2-phenyl-piperidine-3-carboxylicacid ethyl ester

In analogy to the procedure described in Example 47 b),6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylicacid (Example 1 b)) was reacted with ethyl2-phenylpiperidine-3-carboxylate (54529-38-3) in the presence of TBTUand DIEA to obtain the title compound as colorless oil; MS (EI):m/e=500.2 [MH⁺].

Example 68(S)-1-(5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carbonyl)-4,4-difluoro-pyrrolidine-2-carboxylicacid amide

The title compound was synthesized in analogy to Example 47 b, using5-cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid (Example 3c, 50 mg, 214 μmol) and (2S)-4,4-difluoro-2-pyrrolidinecarboxamidehydrochloride (CAN 426844-51-1; 44 mg, 236 μmol) as starting materialsand isolated (63 mg, 80%) as off-white solid; LC-MS (UV peak area, ESI)100%, 366.1629 [MH⁺].

Example 69(2S,4S)-1-(5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carbonyl)-4-fluoro-pyrrolidine-2-carboxylicacid amide

The title compound was synthesized in analogy to Example 47 b, using5-cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid (Example 3c, 50 mg, 214 μmol) and (2S,4S)-4-fluoro-2-pyrrolidinecarboxamidehydrochloride (1:1) (CAN 426844-23-7; 40 mg, 236 μmol) as startingmaterials and isolated (68 mg, 91%) as off-white solid; LC-MS (UV peakarea, ESI) 100%, 348.1721 [MH⁺].

Example 70[6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridin-2-yl]-(hexahydrofuro[2,3-c]pyrrol-5-yl)-methanone

In analogy to the procedure described in Example 47 b),6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylicacid (Example 1 b)) was reacted with hexahydro-2H-furo[3,2-c]pyrrole(1214875-23-6) in the presence of TBTU and DIEA to obtain the titlecompound as colorless oil; MS (EI): m/e=380.5 [MH⁺].

Example 71[6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridin-2-yl]-(2,2-dioxo-2λ6-thia-6-aza-spiro[3.3]hept-6-yl)-methanone

In analogy to the procedure described in Example 47 b),6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylicacid (Example 1 b)) was reacted with 2-thia-6-azaspiro[3.3]heptane,2,2-dioxide (1263182-09-7) in the presence of TBTU and DIEA to obtainthe title compound as colorless oil; MS (EI): m/e=414.5 [MH⁺].

Example 726-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylicacid tert-butyl-(2-carbamoyl-ethyl)-amide

In analogy to the procedure described in Example 47 b),6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylicacid (Example 1 b)) was reacted with 3-(tert-butylamino)propanamide(289656-97-9) in the presence of TBTU and DIEA to obtain the titlecompound as colorless oil; MS (EI): m/e=411.6 [MH⁺].

Example 73(S)-1-(5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carbonyl)-pyrrolidine-2-carboxylicacid amide

The title compound was synthesized in analogy to Example 47 b, using5-cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid (Example 3c, 40 mg, 171 μmol) and (2S)-2-pyrrolidinecarboxamide (CAN 7531-52-4;21.5 mg, 189 μmol) as starting materials and isolated (49 mg, 87%) aswhite solid; LC-MS (UV peak area, ESI) 100%, 330.1818 [MH⁺].

Example 741-[6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carbonyl]-1,8-diaza-spiro[4.5]decane-8-carboxylicacid tert-butyl ester

In analogy to the procedure described in Example 47 b),6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylicacid (Example 1 b)) was reacted with tert-butyl1,8-diazaspiro[4.5]decane-8-carboxylate hydrochloride (851325-42-3) inthe presence of TBTU and DIEA to obtain the title compound as yellowoil; MS (EI): m/e=507.6 [MH⁺].

Example 75(S)-1-{5-Cyclopropyl-6-[(R,S)-1-(tetrahydro-furan-2-yl)methoxy]-pyridine-2-arbonyl}-4,4-difluoro-pyrrolidine-2-carboxylicacid amide

In analogy to the procedure described in Example 47 b),5-cyclopropyl-6-(tetrahydro-furan-2-ylmethoxy)-pyridine-2-carboxylicacid (Example 4 b)) was reacted with(S)-4,4-difluoropyrrolidine-2-carboxamide hydrochloride (CAN426844-51-1) in the presence of TBTU and DIEA to obtain the titlecompound as white solid; MS (EI): m/e=396.5 [MH⁺].

Example 76(S)-1-[5-Cyclopropyl-6-(4-fluoro-benzyl)-pyridine-2-carbonyl]-4,4-difluoro-pyrrolidine-2-carboxylicacid amide

In analogy to the procedure described in Example 47 b),5-cyclopropyl-6-(4-fluoro-benzyl)-pyridine-2-carboxylic acid (Example 5g)) was reacted with (S)-4,4-difluoropyrrolidine-2-carboxamidehydrochloride (CAN 426844-51-1) in the presence of TBTU and DIEA toobtain the title compound as colorless oil; MS (EI): m/e=404.5 [MH⁺].

Example 77(+)-1-[6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carbonyl]-4,4-dimethyl-pyrrolidine-2-carboxylicacid amide

In analogy to the procedure described in Example 47 b),6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylicacid (Example 1 b)) was reacted with4,4-dimethylpyrrolidine-2-carboxamide hydrochloride (Example 90 d) inthe presence of TBTU and DIEA. The mixture of enantiomers was separatedby chiral HPLC (Reprosil Chiral NR). The (+) enantiomer was isolated asyellow solid; MS (EI): m/e=409.6 [MH⁺]; α_(D) ²⁰ (DMSO)=+19.3°.

Example 78(−)-1-[6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carbonyl]-4,4-dimethyl-pyrrolidine-2-carboxylicacid amide

In analogy to the procedure described in Example 47 b),6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylicacid (Example 1 b)) was reacted with4,4-dimethylpyrrolidine-2-carboxamide hydrochloride (Example 90 d) inthe presence of TBTU and DIEA. The mixture of enantiomers was separatedby chiral HPLC (Reprosil Chiral NR). The (−) enantiomer was isolated asyellow solid; MS (EI): m/e=409.6 [MH⁺]; α_(D) ²⁰ (DMSO)=−29.3°.

Example 79(2S,4S)-1-[6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carbonyl]-4-hydroxy-pyrrolidine-2-carboxylicacid amide

In analogy to the procedure described in Example 47 b),6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylicacid (Example 1 b)) was reacted with(2S,4S)-4-hydroxypyrrolidine-2-carboxamide hydrochloride (851233-67-5)in the presence of TBTU and DIEA to obtain the title compound ascolorless oil; MS (EI): m/e=397.5 [MH⁺].

Example 80(2S,4S)-1-[6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carbonyl]-4-fluoro-pyrrolidine-2-carboxylicacid amide

In analogy to the procedure described in Example 47 b),6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylicacid (Example 1 b)) was reacted with(2S,4S)-4-fluoropyrrolidine-2-carboxamide hydrochloride (426844-23-7) inthe presence of TBTU and DIEA to obtain the title compound as whitesolid; MS (EI): m/e=399.4 [MH⁺].

Example 816-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylicacid cyclopropyl-(5-methyl-[1,3,4]oxadiazol-2-ylmethyl)-amide a)Cyclopropyl-(5-methyl-[1,3,4]oxadiazol-2-ylmethyl)-amine

A mixture of cyclopropanamine (765-30-0, 194 mg, 236 μL, 3.39 mmol) and2-(chloromethyl)-5-methyl-1,3,4-oxadiazole (3914-42-9, 90 mg, 679 μmol)was stirred for 16 h at ambient temperature. The mixture wasconcentrated under reduced pressure and the residue taken up inice-water/saturated aqueous Na₂CO₃ solution 1/1 (20 mL) and EtOAc (30mL). The layers were separated and the aqueous layer was extracted onemore time with EtOAc (30 mL). The combined extracts were washed withice-water/brine 1/1 (15 mL), dried over Na₂SO₄ and brought to dryness togive the title compound (36 mg, 35%) as yellow oil which wassufficiently pure to be used in the next reaction step; MS (EI):m/e=154.2 [MH⁺].

b)6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylicacid cyclopropyl-(5-methyl-[1,3,4]oxadiazol-2-ylmethyl)-amide

In analogy to the procedure described in Example 47 b),6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylicacid (Example 1 b)) was reacted withcyclopropyl-(5-methyl-[1,3,4]oxadiazol-2-ylmethyl)-amine in the presenceof TBTU and DIEA to obtain the title compound as colorless oil; MS (EI):m/e=420.6 [MH⁺].

Example 82[6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridin-2-yl]-(3-hydroxy-1-oxa-7-aza-spiro[4.4]non-7-yl)-methanonea) 1-Oxa-7-azaspiro[4.4]nonan-3-ol hydrochloride

A mixture of tert-butyl3-hydroxy-1-oxa-7-azaspiro[4.4]nonane-7-carboxylate (CAN 1331825-50-3,33 mg, 136 μmol) and a 4 M solution of HCl in dioxane (339 μL, 1.36mmol) in dioxane (0.3 mL) was stirred at ambient temperature for 3 h togive the title compound (14 mg, 58%) as light brown oil which wassufficiently pure to be used in the next step; MS (EI): m/e=144.2[(M-Cl)H⁺].

b)[6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridin-2-yl]-(3-hydroxy-1-oxa-7-aza-spiro[4.4]non-7-yl)-methanone

In analogy to the procedure described in Example 47 b),6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylicacid (Example 1 b)) was reacted with 1-oxa-7-azaspiro[4.4]nonan-3-olhydrochloride in the presence of TBTU and DIEA to obtain the titlecompound as yellow oil; MS (EI): m/e=410.5 [MH⁺].

Example 83[6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridin-2-yl]-(7-hydroxy-5-oxa-2-aza-spiro[3.4]oct-2-yl)-methanonea) 7-Hydroxy-5-oxa-2-azonia-spiro[3.4]octane hydrochloride

In analogy to the procedure described in Example 82 a), tert-butyl7-hydroxy-5-oxa-2-azaspiro[3.4]octane-2-carboxylate (which can beprepared in analogy to tert-butyl3-hydroxy-1-oxa-7-azaspiro[4.4]nonane-7-carboxylate (CAN 1331825-50-3)starting from 3-oxoazetidine-1-carboxylic acid tert-butyl ester (CAN398489-26-4) as described in A. I. Moskalenko et al., Russian Journal ofOrganic Chemistry, 47(7), 1091-1096; 2011) was treated with a 4 Msolution of HCl in dioxane to give the title compound as colorless solidwhich was sufficiently pure to be used in the next step; MS (EI):m/e=130.2 [(M-Cl)H⁺].

b)[6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridin-2-yl]-(7-hydroxy-5-oxa-2-aza-spiro[3.4]oct-2-yl)-methanone

In analogy to the procedure described in Example 47 b),6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylicacid (Example 1 b)) was reacted with 5-oxa-2-azaspiro[3.4]octan-7-olhydrochloride in the presence of TBTU and DIEA to obtain the titlecompound as yellow oil; MS (EI): m/e=396.5 [MH⁺].

Example 84[5-Cyclopropyl-6-(2,2,3,3,3-pentafluoro-propoxy)-pyridin-2-yl]-(2,2-dimethyl-pyrrolidin-1-yl)-methanonea) 5-Bromo-6-(2,2,3,3,3-pentafluoro-propoxy)-pyridine-2-carboxylic acid

To a solution of 6-chloro-5-bromo-pyridine-2-carboxylic acid (CAN959958-25-9, 1.7 g, 7.19 mmol) in DMF (90 mL) and THF (30 mL) was addedpotassium tert-butoxide (2.02 g, 18.0 mmol) and2,2,3,3,3-pentafluoropropan-1-ol (5.73 mL, 57.5 mmol). The mixture wasstirred at 140° C. for 4 days, cooled and poured into ice-water (100mL). 2 M Hydrochloric acid (15 mL) was added to adjust the pH to 2-3 andthe mixture was extracted with TBME, organic layers were washed twicewith water, pooled, dried with Na₂SO₄, filtered and concentrated invacuo. The crude material was purified by flash chromatography (silicagel, ethyl acetate/n-heptane gradient) to give the title compound (548mg, 22%) as light-brown solid; LC-MS (UV peak area, ESI) 100%, 347.9306[M−H⁻].

b) 5-Cyclopropyl-6-(2,2,3,3,3-pentafluoro-propoxy)-pyridine-2-carboxylicacid

A mixture of5-bromo-6-(2,2,3,3,3-pentafluoro-propoxy)-pyridine-2-carboxylic acid(501 mg, 1.43 mmol), cyclopropylboronic acid (CAN 411235-57-9, 184 mg,2.15 mmol), palladium diacetate (CAN 3375-31-3, 16.1 mg, 71.6 μmol),tricyclohexylphosphine (CAN 2622-14-2, 8.03 mg, 28.6 μmol) and potassiumphosphate (1.06 g, 5.01 mmol) in toluene/water (20/1 v/v, 10.5 mL) wasstirred at 100° C. for 22 hours. After cooling the mixture was pouredinto ice-water (80 mL). 2 M Hydrochloric acid (25 mL) was added and themixture was extracted with TBME, organic layers were washed twice withwater, pooled, dried with Na₂SO₄, filtered and concentrated in vacuo.The crude material was purified by flash chromatography (silica gel,ethyl acetate/n-heptane gradient) to give the title compound (340 mg,76%) as off-white solid; LC-MS (UV peak area, ESI) 96.6%, 310.0513[M−H⁻].

c)[5-Cyclopropyl-6-(2,2,3,3,3-pentafluoro-propoxy)-pyridin-2-yl]-(2,2-dimethyl-pyrrolidin-1-yl)-methanone

The title compound was synthesized in analogy to Example 47 b, using5-cyclopropyl-6-(2,2,3,3,3-pentafluoro-propoxy)-pyridine-2-carboxylicacid (40 mg, 129 μmol) and 2,2-dimethylpyrrolidine (CAN 35018-15-6; 18μL, 141 μmol) as starting materials and isolated (41 mg, 81%) aslight-brown oil; LC-MS (UV peak area, ESI) 100%, 393.1611 [MH⁺].

Example 85[6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridin-2-yl]-(1S,5R)-8-oxa-3-aza-bicyclo[3.2.1]oct-3-yl-methanone

In analogy to the procedure described in Example 47 b),6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylicacid (Example 1 b)) was reacted with(1R,5S)-8-oxa-3-azabicyclo[3.2.1]octane hydrochloride (54745-74-3) inthe presence of TBTU and DIEA to obtain the title compound as colorlessoil; MS (EI): m/e=380.5 [MH⁺].

Example 86[6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridin-2-yl]-(1R,5S)-3-oxa-8-aza-bicyclo[3.2.1]oct-8-yl-methanone

In analogy to the procedure described in Example 47 b),6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylicacid (Example 1 b)) was reacted with(1R,5S)-3-oxa-8-azabicyclo[3.2.1]octane hydrochloride (904316-92-3) inthe presence of TBTU and DIEA to obtain the title compound as colorlessoil; MS (EI): m/e=380.6 [MH⁺].

Example 87(R)-1-[5-Cyclopropyl-6-(2,2,3,3,3-pentafluoro-propoxy)-pyridine-2-carbonyl]-4,4-difluoro-pyrrolidine-2-carboxylicacid amide

The title compound was synthesized in analogy to Example 47 b, using5-cyclopropyl-6-(2,2,3,3,3-pentafluoro-propoxy)-pyridine-2-carboxylicacid (30 mg, 96 μmol) and (2R)-4,4-difluoropyrrolidine-2-carboxamidehydrochloride (CAN 1315053-41-8; 19.8 mg, 106 μmol) as startingmaterials and isolated (38 mg, 89%) as white solid; LC-MS (UV peak area,ESI) 97%, 444.1155 [MH⁺].

Example 881-(5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carbonyl)-piperidine-2-carboxylicacid amide

The title compound was synthesized in analogy to Example 47 b, using5-cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid (Example 3c, 100 mg, 429 μmol) and 2-piperidinecarboxamide (CAN 19889-77-1, 60.4mg, 472 μmol) as starting materials and isolated (135 mg, 92%) as whitesolid; LC-MS (UV peak area, ESI) 100%, 344.1972 [MH⁺].

Example 894-(5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carbonyl)-thiomorpholine-3-carboxylicacid amide

The title compound was synthesized in analogy to Example 47 b, using5-cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid (Example 3c, 100 mg, 429 μmol) and 3-thiomorpholinecarboxamide (CAN 103742-31-0,68.9 mg, 472 μmol) as starting materials and isolated (119 mg, 77%) aswhite solid; LC-MS (UV peak area, ESI) 100%, 362.1540 [MH⁺].

Example 901-(5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carbonyl)-4,4-dimethyl-pyrrolidine-2-carboxylicacid amide a) 4,4-Dimethyl-pyrrolidine-1,2-dicarboxylic acid1-tert-butylester

To a solution of 4,4-dimethyl-proline (1.7 g, 11.8 mmol) in dry dioxane(29 mL) and water (24 mL) was added 1 N sodium hydroxide solution (9 mL)followed by slow addition of di-tert-butyldicarbonate (1.80 g, 8.2 mmol)dissolved in dioxane (5 mL) at ambient temperature. Additional 1 Nsodium hydroxide solution (3 mL) was added and the mixture was stirredovernight. Additional di-tert-butyldicarbonate (1.80 g, 8.2 mmol)dissolved in dioxane (5 mL) was added and stirring continued for 3hours. The mixture was concentrated, 1 N sodium bisulfite solution (22mL) was added and the suspension was extracted with ethyl acetate.Organic phases were washed with water and brine, combined, dried overMgSO₄, filtered and concentrated. The solid was crystallized fromdiethylether by addition of heptane and dried in vacuo to give the titlecompound (2.54 g, 89%) as white crystalline solid; MS (ESI) 242.0[M−H⁻].

b) 4,4-Dimethyl-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester2-(2,5-dioxo-pyrrolidin-1-yl) ester

A solution of 4,4-dimethyl-pyrrolidine-1,2-dicarboxylic acid1-tert-butylester (2.0 g, 8.22 mmol) in THF (20 mL) was cooled to 0° C.To the cold solution was added N-hydroxysuccinimide (1.2 g, 10.4 mmol)and diisopropylcarbodiimide (1.32 g, 10.4 mmol). Cooling was removed andthe mixture stirred for 3 hours at room temperature. The urea wasfiltered off, washed with diethylether and the filtrates wereconcentrated. The residue was partitioned between ethyl acetate and coldwater; organic phases were washed with cold brine, combined, dried withMgSO₄, filtered and concentrated in vacuo. The residue was purified byflash chromatography (silica, heptane/ethyl acetate 9:1) to give thetitle compound (1.95 g, 70%) as colorless oil; MS (ESI) 341.1 [MH⁺].

b) 2-Carbamoyl-4,4-dimethyl-pyrrolidine-1-carboxylic acid tert-butylester

A solution of 4,4-dimethyl-pyrrolidine-1,2-dicarboxylic acid1-tert-butyl ester 2-(2,5-dioxo-pyrrolidin-1-yl) ester (1.9 g, 5.58mmol) in DCM (20 mL) was cooled to 0° C. Gaseous ammonia was bubbled for15 minutes through the cold solution, and stirring was continued for 1hour in the cold. The succinimide was filtered off, washed with DCM andthe filtrates were partitioned between ethyl acetate and cold brine;organic phases were combined, dried with Na₂SO₄, filtered andconcentrated in vacuo. The residue was purified by flash chromatography(silica, ethyl acetate) to give the title compound (1.33 g, 98%) ascolorless foam; MS (ESI) 243.1 [MH⁺].

d) 4,4-Dimethyl-pyrrolidine-2-carboxylic acid amide hydrochloride

A solution of 2-carbamoyl-4,4-dimethyl-pyrrolidine-1-carboxylic acidtert-butyl ester (1.2 g, 4.95 mmol) in dioxane (5 mL) was cooled to 10°C. Hydrogen chloride dissolved in dioxane (10 mL, 6.4 N) was added andthe mixture was stirred for 1.5 hours. Diethylether (50 mL) was added tocompletely precipitate the product, which was filtered and dried to givethe title compound (0.84 g, 95%) as colorless solid; MS (ESI) 143.0[MH⁺].

e)1-(5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carbonyl)-4,4-dimethyl-pyrrolidine-2-carboxylicacid amide

The title compound was synthesized in analogy to Example 47 b, using5-cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid (Example 3c, 100 mg, 429 μmol) and 4,4-dimethyl-pyrrolidine-2-carboxylic acidamide hydrochloride (84.3 mg, 472 μmol) as starting materials andisolated (145 mg, 95%) as white foam; LC-MS (UV peak area, ESI) 100%,358.2124 [MH⁺].

Example 91(+)-1-(5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carbonyl)-piperidine-2-carboxylicacid amide

The enantiomers of1-(5-cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carbonyl)-piperidine-2-carboxylicacid amide (Example 88) were separated by chiral HPLC (Reprosil ChiralNR, 25% ethanol in n-heptane). The (+) enantiomer (47 mg, 40%) wasisolated as white solid; LC-MS (UV peak area/ESI) 100%, 344.1976 [MH⁺];(+) enantiomer, ˜100% ee; α_(D) ²⁰ (MeOH)=+24.8°.

Example 92(−)-1-(5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carbonyl)-piperidine-2-carboxylicacid amide

The enantiomers of1-(5-cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carbonyl)-piperidine-2-carboxylicacid amide (Example 88) were separated by chiral HPLC (Reprosil ChiralNR, 25% ethanol in n-heptane). The (−) enantiomer (47 mg, 40%) wasisolated as white solid; LC-MS (UV peak area/ESI) 100%, 344.1966 [MH⁺];(−) enantiomer, ˜100% ee; α_(D) ²⁰ (MeOH)=−26.5°.

Example 93(−)-4-(5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carbonyl)-thiomorpholine-3-carboxylicacid amide

The enantiomers of4-(5-cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carbonyl)-thiomorpholine-3-carboxylicacid amide (Example 89) were separated by chiral HPLC (Reprosil ChiralNR, 30% ethanol in n-heptane). The (−) enantiomer (49 mg, 47%) wasisolated as white solid; LC-MS (UV peak area/ESI) 100%, 362.1541 [MH⁺];(−) enantiomer, ˜100% ee.

Example 94(+)-1-(5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carbonyl)-4,4-dimethyl-pyrrolidine-2-carboxylicacid amide

The enantiomers of1-(5-cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carbonyl)-4,4-dimethyl-pyrrolidine-2-carboxylicacid amide (Example 90 e) were separated by chiral HPLC (Reprosil ChiralNR, 20% ethanol in n-heptane). The (+) enantiomer (65 mg, 49%) wasisolated as white foam; LC-MS (UV peak area/ESI) 100%, 358.2125 [MH⁺];(+) enantiomer, ˜79% ee; α_(D) ²⁰ (MeOH)=+56.9°.

Example 95(−)-1-(5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carbonyl)-4,4-dimethyl-pyrrolidine-2-carboxylicacid amide

The enantiomers of1-(5-cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carbonyl)-4,4-dimethyl-pyrrolidine-2-carboxylicacid amide (Example 90 e) were separated by chiral HPLC (Reprosil ChiralNR, 20% ethanol in n-heptane). The (−) enantiomer (50 mg, 38%) wasisolated as white foam; LC-MS (UV peak area/ESI) 100%, 358.2133 [MH⁺];(−) enantiomer, ˜99.5% ee; α_(D) ²⁰ (MeOH)=−89.0°.

Example 963-(5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carbonyl)-thiazolidine-4-carboxylicacid amide

The title compound was synthesized in analogy to Example 47 b, using5-cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid (Example 3c, 100 mg, 429 μmol) and 4-thiazolidinecarboxamide (CAN 103749-87-7,62.3 mg, 472 μmol) as starting materials and isolated (114 mg, 77%) aswhite solid; LC-MS (UV peak area, ESI) 100%, 348.1377 [MH⁺].

Example 97(−)-3-(5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carbonyl)-thiazolidine-4-carboxylicacid amide

The enantiomers of3-(5-cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carbonyl)-thiazolidine-4-carboxylicacid amide (Example 96) were separated by chiral HPLC (Reprosil ChiralNR, 40% ethanol in n-heptane). The (−) enantiomer (48 mg, 48%) wasisolated as white solid; LC-MS (UV peak area/ESI) 97.9%, 348.1378 [MH⁺];(−) enantiomer, ˜100% ee.

Example 981-[6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carbonyl]-4,4-dimethyl-pyrrolidine-2-carboxylicacid amide

In analogy to the procedure described in Example 47 b),6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylicacid (Example 1 b)) was reacted with4,4-dimethyl-pyrrolidine-2-carboxylic acid amide hydrochloride (Example90 d)) in the presence of TBTU and DIEA to obtain the title compound ascolorless oil; MS (EI): m/e=380.6 [MH⁺].

Example 99[6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridin-2-yl]-(5-oxa-2-aza-spiro[3.4]oct-2-yl)-methanone

In analogy to the procedure described in Example 47 b),6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylicacid (Example 1 b)) was reacted with 5-oxa-2-azaspiro[3.4]octanehydrochloride (1359656-11-3) in the presence of TBTU and DIEA to obtainthe title compound as colorless oil; MS (EI): m/e=380.5 [MH⁺].

Example 100[6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridin-2-yl]-(1-oxa-7-aza-spiro[4.4]non-7-yl)-methanone

In analogy to the procedure described in Example 47 b),6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylicacid (Example 1 b)) was reacted with 1-oxa-7-azaspiro[4.4]nonane(176-12-5) in the presence of TBTU and DIEA to obtain the title compoundas colorless oil; MS (EI): m/e=394.5 [MH⁺].

Example 101(5-Aza-spiro[3.4]oct-5-yl)-[6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridin-2-yl]-methanone

In analogy to the procedure described in Example 47 b),6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylicacid (Example 1 b)) was reacted with 5-azaspiro[3.4]octane (52876-78-5)in the presence of TBTU and DIEA to obtain the title compound ascolorless oil; MS (EI): m/e=378.5 [MH⁺].

Example 102[6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridin-2-yl]-(3,3-difluoro-azetidin-1-yl)-methanone

In analogy to the procedure described in Example 47 b),6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylicacid (Example 1 b)) was reacted with 3,3-difluoroazetidine hydrochloride(CAN 288315-03-7) in the presence of TBTU and DIEA to obtain the titlecompound as colorless solid; MS (EI): m/e=360.4 [MH⁺].

Example 103[6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridin-2-yl]-(1,1-difluoro-5-aza-spiro[2.4]hept-5-yl)-methanone

In analogy to the procedure described in Example 47 b),6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylicacid (Example 1 b)) was reacted with 1,1-difluoro-5-azaspiro[2.4]heptanehydrochloride (1215071-12-7) in the presence of TBTU and DIEA to obtainthe title compound as colorless solid; MS (EI): m/e=400.5 [MH⁺].

Example 104(5-Aza-spiro[2.4]hept-5-yl)-[6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridin-2-yl]-methanone

In analogy to the procedure described in Example 47 b),6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylicacid (Example 1 b)) was reacted with 5-azaspiro[2.4]heptanehydrochloride (3659-21-0) in the presence of TBTU and DIEA to obtain thetitle compound as colorless oil; MS (EI): m/e=364.5 [MH⁺].

Example 1056-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylicacid cyclopropylmethyl-methyl-amide

In analogy to the procedure described in Example 47 b),6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylicacid (Example 1 b)) was reacted with 1-cyclopropyl-N-methylmethanaminehydrochloride (77335-18-3) in the presence of TBTU and DIEA to obtainthe title compound as colorless oil; MS (EI): m/e=352.4 [MH⁺].

Example 106[6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridin-2-yl]-(4-cyclopropylmethyl-piperazin-1-yl)-methanone

In analogy to the procedure described in Example 47 b),6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylicacid (Example 1 b)) was reacted with 1-(cyclopropylmethyl)piperazine(57184-25-5) in the presence of TBTU and DIEA to obtain the titlecompound as colorless oil; MS (EI): m/e=407.6 [MH⁺].

Example 1073-[6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carbonyl]-3-aza-bicyclo[3.1.0]hexane-6-carboxylicacid ethyl ester

In analogy to the procedure described in Example 47 b),6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylicacid (Example 1 b)) was reacted with ethyl3-azabicyclo[3.1.0]hexane-6-carboxylate (179236-79-4) in the presence ofTBTU and DIEA to obtain the title compound as colorless oil; MS (EI):m/e=422.5 [MH⁺].

Example 1081-[6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carbonyl]-pyrrolidine-2-carboxylicacid methyl ester

In analogy to the procedure described in Example 47 b),6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylicacid (Example 1 b)) was reacted with methyl pyrrolidine-2-carboxylatehydrochloride (79397-50-5) in the presence of TBTU and DIEA to obtainthe title compound as colorless oil; MS (EI): m/e=396.5 [MH⁺].

Example 1094-[6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carbonyl]-piperazine-1-carboxylicacid benzyl ester

In analogy to the procedure described in Example 47 b),6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylicacid (Example 1 b)) was reacted with benzyl piperazine-1-carboxylate(31166-44-6) in the presence of TBTU and DIEA to obtain the titlecompound as light brown oil; MS (EI): m/e=487.5 [MH⁺].

Example 1103-[6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carbonyl]-3-aza-bicyclo[3.1.0]hexane-6-carboxylicacid

In analogy to the procedure described in Example 24,3-[6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carbonyl]-3-aza-bicyclo[3.1.0]hexane-6-carboxylicacid ethyl ester (Example 107) was saponified to give the title compoundas colorless solid; MS (EI): m/e=394.5 [MH⁺].

Example 1111-[5-Cyclopropyl-6-(4-fluoro-benzyl)-pyridine-2-carbonyl]-1,8-diaza-spiro[4.5]decane-8-carboxylicacid tert-butyl ester

In analogy to the procedure described in Example 47 b),5-cyclopropyl-6-(4-fluoro-benzyl)-pyridine-2-carboxylic acid (Example 5g)) was reacted with tert-butyl 1,8-diazaspiro[4.5]decane-8-carboxylate(937729-06-1) in the presence of TBTU and DIEA to obtain the titlecompound as colorless oil; MS (EI): m/e=494.6 [MH⁺].

Example 112(−)-3-[6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carbonyl]-thiazolidine-4-carboxylicacid amide

In analogy to the procedure described in Example 47 b),6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylicacid (Example 1 b)) was reacted with and 4-thiazolidinecarboxamide (CAN103749-87-7) in the presence of TBTU and DIEA. The mixture ofenantiomers was separated by chiral HPLC (Reprosil Chiral NR). The (−)enantiomer was isolated as white solid; MS (EI): m/e=399.4 [MH⁺]; α_(D)²⁰ (DMSO)=−547.6°.

Example 113[5-Cyclopropyl-6-(4-fluoro-benzyl)-pyridin-2-yl]-(1,8-diaza-spiro[4.5]dec-1-yl)-methanone

A solution of tert-butyl1-(5-cyclopropyl-6-(4-fluorobenzyl)picolinoyl)-1,8-diazaspiro[4.5]decane-8-carboxylate(Example 111, 19 mg, 38.5 μmol) and 2,2,2-trifluoroacetic acid (43.9 mg,29.5 μL, 385 μmol) in DCM (0.4 mL) was stirred for 12 h at ambienttemperature. The reaction mixture was poured onto 20 mL saturatedaqueous NaHCO₃ solution/ice and extracted with EtOAc (2×20 mL). Thecombined extracts were washed with ice-water/brine (20 mL), dried overNa₂SO₄ and brought to dryness to give the title compound (14 mg, 92%) ascolorless oil; MS (EI): m/e=394.5 [MH⁺].

Example 1141-[6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carbonyl]-pyrrolidine-2-carboxylicacid amide a)1-(6-(Cyclopropylmethoxy)-5-(3,3-difluoroazetidin-1-yl)picolinoyl)pyrrolidine-2-carboxylicacid

In analogy to the procedure described in Example 24,1-[6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carbonyl]-pyrrolidine-2-carboxylicacid methyl ester (Example 108) was saponified to give the titlecompound as colorless solid; MS (EI): m/e=382.5 [MH⁺].

b)1-[6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carbonyl]-pyrrolidine-2-carboxylicacid amide

To an ice-cold solution of1-(6-(cyclopropylmethoxy)-5-(3,3-difluoroazetidin-1-yl)picolinoyl)pyrrolidine-2-carboxylicacid (8.6 mg, 22.6 μmol) in DMF (2 mL) was added carbonyldiimidazole(10.2 mg, 63.1 μmol). After 5 minutes the reaction mixture was warmed toambient temperature and stirred for 2 h. NH₃ gas was bubbled through thesolution for 10 minutes and stirring was continued for 12 h. Thereaction mixture was poured onto ice-water (20 mL) and extracted withEtOAc (2×20 mL). The combined extracts were dried over Na₂SO₄ andconcentrated in vacuo to give the title compound (9 mg, quant.) ascolorless wax; MS (EI): m/e=381.5 [MH⁺].

Example 115(−)-3-(5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carbonyl)-1,1-dioxo-1λ⁶-thiazolidine-4-carboxylicacid amide

To a suspension of(−)-3-(5-cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carbonyl)-thiazolidine-4-carboxylicacid amide (Example 97, 60 mg, 173 μmol) in DCM (6 mL) was added m-CPBA(65.6 mg, 380 μmol) and the reaction mixture was stirred at roomtemperature for 3 hours. 1 N sodium hydroxide solution (3 mL) was addedand the mixture was dried by filtration over ChemElut® and concentratedin vacuo. The residue was purified by flash chromatography (silica,DCM/methanol 0-5%) to give the title compound (21 mg, 32%) as whitesolid; LC-MS (UV peak area/ESI) 100%, 380.1286 [MH⁺].

Example 116(1S,4R)-3-(5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carbonyl)-1-oxo-1λ⁴-thiazolidine-4-carboxylicacid amide or(1R,4S)-3-(5-cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carbonyl)-1-oxo-1λ⁴-thiazolidine-4-carboxylicacid amide

To a suspension of(−)-3-(5-cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carbonyl)-thiazolidine-4-carboxylicacid amide (Example 97, 60 mg, 173 μmol) in DCM (6 mL) was added m-CPBA(65.6 mg, 380 μmol) and the reaction mixture was stirred at roomtemperature for 3 hours. 1 N sodium hydroxide solution (3 mL) was addedand the mixture was dried by filtration over ChemElut® and concentratedin vacuo. The residue was purified by flash chromatography (silica,DCM/methanol 0-5%) to give the title compound (30 mg, 48%) as whitesolid; LC-MS (UV peak area/ESI) 95.8%, 364.1335 [MH⁺].

Example 117(+)-3-(5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carbonyl)-1,1-dioxo-1λ⁶-thiazolidine-4-carboxylicacid amide a)(+)-3-(5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carbonyl)-thiazolidine-4-carboxylicacid amide

The enantiomers of3-(5-cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carbonyl)-thiazolidine-4-carboxylicacid amide (Example 96) were separated by chiral HPLC (Reprosil ChiralNR, 40% ethanol in n-heptane). The (+) enantiomer (34 mg, 34%) wasisolated as white solid; LC-MS (UV peak area/ESI) 100%, 348.1380 [MH⁺];(+) enantiomer, ˜100% ee.

b)(+)-3-(5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carbonyl)-1,1-dioxo-1λ⁶-thiazolidine-4-carboxylicacid amide

To a suspension of(+)-3-(5-cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carbonyl)-thiazolidine-4-carboxylicacid amide (60 mg, 173 μmol) in DCM (6 mL) was added m-CPBA (65.6 mg,380 μmol) and the reaction mixture was stirred at room temperature forover night. 1 N sodium hydroxide solution (3 mL) was added and themixture was dried by filtration over ChemElut® and concentrated invacuo. The residue was purified by flash chromatography (silica,DCM/methanol 0-5%) to give the title compound (31 mg, 47%) as whitesolid; LC-MS (UV peak area/ESI) 99.0%, 380.1279 [MH⁺].

Example 118[6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridin-2-yl]-(3,3,4,4-tetrafluoro-pyrrolidin-1-yl)-methanone

In analogy to the procedure described in Example 47 b),6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylicacid (Example 1 b)) was reacted with 3,3,4,4-tetrafluoropyrrolidinehydrochloride (1810-13-5) in the presence of TBTU and DIEA to obtain thetitle compound as colorless oil; MS (EI): m/e=410.5 [MH⁺].

Example 119[6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridin-2-yl]-(2,6-dimethyl-morpholin-4-yl)-methanone

In analogy to the procedure described in Example 47 b),6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylicacid (Example 1 b)) was reacted with 2,6-dimethylmorpholine (141-91-3)in the presence of TBTU and DIEA to obtain the title compound ascolorless oil; MS (EI): m/e=382.5 [MH⁺].

Example 120(R)-3-[6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carbonyl]-5,5-dimethyl-thiazolidine-4-carboxylicacid amide a) (R)-5,5-Dimethylthiazolidine-4-carboxamide hydrochloride

In analogy to the procedure described in Example 114 b),(R)-3-(tert-butoxycarbonyl)-5,5-dimethylthiazolidine-4-carboxylic acid(CAN 117918-23-7) was converted to the title compound in the form of acolorless solid; MS (EI): m/e=260 [M⁺].

b) (R)-5,5-Dimethylthiazolidine-4-carboxamide hydrochloride

In analogy to the procedure described in Example 82 a), (R)-tert-butyl4-carbamoyl-5,5-dimethylthiazolidine-3-carboxylate was treated with a 4M solution of HCl in dioxane to give the title compound as yellow solidwhich was sufficiently pure to be used in the next step; MS (EI):m/e=161.2 [(M-Cl)H⁺].

c)(R)-3-[6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carbonyl]-5,5-dimethyl-thiazolidine-4-carboxylicacid amide

In analogy to the procedure described in Example 47 b),6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylicacid (Example 1 b)) was reacted with(R)-5,5-dimethylthiazolidine-4-carboxamide hydrochloride in the presenceof TBTU and DIEA to obtain the title compound as light yellow solid; MS(EI): m/e=427.4 [MH⁺].

Example 121(S)-1-[6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carbonyl]-5,5-dimethyl-pyrrolidine-2-carboxylicacid amide a) (S)-5,5-Dimethylpyrrolidine-2-carboxamide hydrochloride

In analogy to the procedure described in Example 82 a), (S)-tert-butyl5-carbamoyl-2,2-dimethylpyrrolidine-1-carboxylate (CAN 1292838-05-1) wastreated with a 4 M solution of HCl in dioxane to give the title compoundas colorless solid which was sufficiently pure to be used in the nextstep; MS (EI): m/e=143.2 [(M-Cl)H⁺].

b)(S)-1-[6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carbonyl]-5,5-dimethyl-pyrrolidine-2-carboxylicacid amide

In analogy to the procedure described in Example 47 b),6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylicacid (Example 1 b)) was reacted with(S)-5,5-dimethylpyrrolidine-2-carboxamide hydrochloride in the presenceof TBTU and DIEA to obtain the title compound as colorless foam; MS(EI): m/e=409.5 [MH⁺].

Example 1223-[6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carbonyl]-thiazolidine-4-carboxylicacid amide

In analogy to the procedure described in Example 47 b),6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylicacid (Example 1 b)) was reacted with and 4-thiazolidinecarboxamide (CAN103749-87-7) in the presence of TBTU and DIEA to obtain the titlecompound as white solid; MS (EI): m/e=399.5 [MH⁺].

Example 123(2S,4R)-1-[5-Cyclopropyl-6-(cyclopropylmethoxy)pyridine-2-carbonyl]-4-fluoropyrrolidine-2-carboxamide

In analogy to the procedure described in Example 47 b),5-cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid (Example 3c, 50 mg, 214 μmol) was reacted with(2S,4R)-4-fluoropyrrolidine-2-carboxamide hydrochloride (CAN796884-06-5, 39.8 mg, 236 μmol) to obtain the title compound (54 mg,73%) as white solid; LC-MS (UV peak area, ESI) 100%, 348.1727 [MH⁺].

Example 1243-[6-(Cyclopropylmethoxy)-5-(3,3-difluoroazetidin-1-yl)pyridine-2-carbonyl]-1-oxo-1,3-thiazolidine-4-carboxamide

3-Chloroperbencoic acid (172 mg, 994 μmol) was added to a solution of3-[6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carbonyl]-thiazolidine-4-carboxylicacid amide (Example 122, 180 mg, 452 μmol) in dichloromethane (1.8 mL).The reaction mixture was stirred for 12 h at ambient temperature, pouredonto sodiumthiosulfate/ice water (1×15 mL) and extracted with EtOAc(2×20 mL). The combined extracts were washed with ice/brine (1×25 mL),dried over Na₂SO₄ and filtered. The solvent was removed under reducedpressure and the residue purified by prep. HPLC (methanol/formic acid95/5) to give the title compound (9 mg, 5%) as light yellow solid; MS(EI): m/e=415.4 [MH⁺].

Example 1253-[6-(Cyclopropylmethoxy)-5-(3,3-difluoroazetidin-1-yl)pyridine-2-carbonyl]-1,1-dioxo-1,3-thiazolidine-4-carboxamide

3-Chloroperbencoic acid (172 mg, 994 μmol) was added to a solution of3-[6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carbonyl]-thiazolidine-4-carboxylicacid amide (Example 122, 180 mg, 452 μmol) in dichloromethane (1.8 mL).The reaction mixture was stirred for 12 h at ambient temperature, pouredonto sodiumthiosulfate/ice water (1×15 mL) and extracted with EtOAc(2×20 mL). The combined extracts were washed with ice/brine (1×25 mL),dried over Na₂SO₄ and filtered. The solvent was removed under reducedpressure and the residue purified by prep. HPLC (methanol/formic acid95/5) to give the title compound (9 mg, 5%) as light yellow solid; MS(EI): m/e=431.4 [MH⁺].

Example 126(2S,4R)-1-[6-(Cyclopropylmethoxy)-5-(3,3-difluoroazetidin-1-yl)pyridine-2-carbonyl]-4-fluoropyrrolidine-2-carboxamide

In analogy to the procedure described in Example 47 b),6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylicacid (Example 1 b, 25 mg, 87.9 μmol) was reacted with(2S,4R)-4-fluoropyrrolidine-2-carboxamide hydrochloride (CAN796884-06-5, 17.8 mg, 106 μmol) to obtain the title compound (17 mg,49%) as white solid; MS (EI): m/e=399.4 [MH⁺].

Example 127(−)-3-[6-(Cyclopropylmethoxy)-5-(3,3-difluoroazetidin-1-yl)pyridine-2-carbonyl]-1,1-dioxo-1,3-thiazolidine-4-carboxamide

a) O3-tert-Butyl O4-methyl 1,1-dioxo-1,3-thiazolidine-3,4-dicarboxylate

3-Chloroperbenzoic acid (698 mg, 4.04 mmol) was added to an ice coldsolution of O3-tert-butyl O4-methyl thiazolidine-3,4-dicarboxylate (CAN63664-10-8, 0.5 g, 2.02 mmol) in dichloromethane (4 mL). The suspensionwas stirred for 2 h at ambient temperature. Additional3-chloroperbenzoic acid (349 mg, 2.02 mmol) was added and stirring wascontinued for 12 h at ambient temperature. The reaction mixture waspoured onto ice water/saturated NaHCO₃-solution (50 mL) and the layerswere separate. The aqueous layer was extracted with dichloromethane(2×50 mL). The combined organic layers were washed with ice water/brine(30 mL), dried over Na₂SO₄ and concentrated in vacuo to give a yellowoil which was purified by column chromatography (20 g silicagel,heptane/AcOEt 0-20% in 120 min) to obtain the title compound (362 mg,64%) as colorless liquid, MS (ESI) m/e=180.1 [MH-Boc⁺].

b) 3-tert-Butoxycarbonyl-1,1-dioxo-1,3-thiazolidine-4-carboxylic acid

A solution of O3-tert-butyl O4-methyl1,1-dioxo-1,3-thiazolidine-3,4-dicarboxylate (Example 127 a, 0.35 g,1.25 mmol) and lithium hydroxide hydrate (63.1 mg, 1.5 mmol) in THF (3.5mL) and water (1.05 mL) was stirred for 20 h at ambient temperature. Thereaction mixture was poured onto ice/0.1N HCl (25 mL) and extracted withEtOAc (2×25 mL). The combined extracts were washed with ice/brine (1×25mL), dried over Na₂SO₄ and filtered. The solvent was removed underreduced pressure to give the title compound (306 mg, 92%) as colorlessfoam, MS (ESI) m/e=264.05 [M−H⁻].

c) tert-Butyl 4-carbamoyl-1,1-dioxo-1,3-thiazolidine-3-carboxylate

Carbonyldiimidazole (520 mg, 3.21 mmol) was added to an ice coldsolution of3-tert-butoxycarbonyl-1,1-dioxo-1,3-thiazolidine-4-carboxylic acid(Example 127 b, 304 mg, 1.15 mmol) in DMF (1 mL). After 5 min. themixture was warmed to ambient temperature and stirred for 2 h. GaseousNH₃ was bubbled for 10 min through the solution while the temperaturewas kept below 20° C. Stirring was continued for 12 h at ambienttemperature. The reaction mixture was poured into 30 mL ice/water/1N HCland extracted with EtOAc (2×30 mL). The combined extracts were washedwith ice/brine (20 mL), dried over Na₂SO₄ and concentrated in vacuo togive the title compound (197 mg, 65%) as white solid, MS (ESI) m/e=263.1[M−H⁻].

d) 1,1-Dioxo-1,3-thiazolidine-4-carboxamide hydrochloride

An ice cold 4 M solution of HCl in dioxane (4.73 mL, 18.9 mmol) wasadded to a solution of tert-butyl4-carbamoyl-1,1-dioxo-1,3-thiazolidine-3-carboxylate (Example 127 c, 500mg, 1.89 mmol) in dichloromethane (10.2 mL). The mixture was stirred for4 d at ambient temperature. Removal of the solvent in vacuo yielded thetitle compound (388 mg, quant.) as white solid which was used in thenext step without further purification, MS (ESI) m/e=198.99 [M−H⁻].

e)(−)-3-[6-(Cyclopropylmethoxy)-5-(3,3-difluoroazetidin-1-yl)pyridine-2-carbonyl]-1,1-dioxo-1,3-thiazolidine-4-carboxamide

A solution of6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylicacid (Example 1 b, 200 mg, 704 μmol),1,1-dioxo-1,3-thiazolidine-4-carboxamide hydrochloride (Example 127 d,169 mg, 844 μmol), 2-bromo-1-ethylpyridinium tetrafluoroborate (212 mg,774 μmol) and DIEA (273 mg, 361 μL, 2.11 mmol) in THF (20 mL) wasstirred for 24 h at ambient temperature. The solvent was removed underreduced pressure, ice/sat. aqueous NaHCO₃ (75 mL) and EtOAc (75 mL) wereadded and the layers were separated. The aqueous layer was extractedwith EtOAc (75 mL). The combined extracts were washed with ice/0.1N HCl(75 mL) and ice/brine (75 mL), dried over Na₂SO₄ and filtered. Thesolvent was removed under reduced pressure to give a yellow solid whichwas recrystallized from EtOAc (3 mL). The crude product was purified bychiral HPLC (Reprosil Chiral NR, EtOH/heptane 40%/60%) to give the titlecompound (63 mg, 21%) as colorless oil, MS (EI): m/e=431.3 [MH⁺].

Example 1283-[6-(Cyclopropylmethoxy)-5-(3-methoxyazetidin-1-yl)pyridine-2-carbonyl]-1,1-dioxo-1,3-thiazolidine-4-carboxamide

a)6-(Cyclopropylmethoxy)-5-(3-methoxyazetidin-1-yl)pyridine-2-carboxylicacid

Under a nitrogen atmosphere, 3-methoxyazetidine (38 mg, 0.44 mmol),BINAP (23 mg, 0.037 mmol), Pd₂(dba)₃ (17 mg, 0.02 mmol) and Cs₂CO₃ (240mg, 0.735 mmol) were added to a solution of5-bromo-6-(cyclopropylmethoxy)pyridine-2-carboxylic acid (CAN1415898-37-1, 100 mg, 0.37 mmol) in toluene (4 mL). The reaction mixturewas stirred overnight at 110° C. and then concentrated under reducedpressure. The residue was dissolved in water and extracted with ethylacetate (30 mL). The aqueous layer was adjusted to pH 2 by addition of1N HCl. The resulting precipitate was collected by filtration and driedin vacuo. Chromatographical purification over silica gel using petroleumether/ethyl acetate=1/2 provided the title compound (35 mg, 34%) as ayellow solid, LC-MS: 265.2 [MH⁺].

b)3-[6-(Cyclopropylmethoxy)-5-(3-methoxyazetidin-1-yl)pyridine-2-carbonyl]-1,1-dioxo-1,3-thiazolidine-4-carboxamide

In analogy to the procedure described in Example 127 e),6-(cyclopropylmethoxy)-5-(3-methoxyazetidin-1-yl)pyridine-2-carboxylicacid (Example 128 a, 30 mg, 108 μmol) was reacted with1,1-dioxo-1,3-thiazolidine-4-carboxamide hydrochloride (Example 127 d,26.0 mg, 129 μmol) to give the title compound (15 mg, 33%) as off-whitesolid, MS (EI): m/e=425.5 [MH⁺].

Example 129(2S)-1-[6-(Cyclopropylmethoxy)-5-(1-hydroxycyclobutyl)pyridine-2-carbonyl]-4,4-difluoropyrrolidine-2-carboxamide

In analogy to the procedure described in Example 127 e),6-(cyclopropylmethoxy)-5-(1-hydroxycyclobutyl)pyridine-2-carboxylic acid(CAN 1415899-53-4, 15 mg, 57 μmol) was reacted with(S)-4,4-difluoropyrrolidine-2-carboxamide hydrochloride (CAN426844-51-1, 10.6 mg, 57 μmol) to give the title compound (6 mg, 21%) aslight yellow oil, LC-MS (UV peak area, ESI) 100%, 396.1740 [MH⁺].

Example 130(2S)-1-[6-(Cyclopropylmethoxy)-5-(1-fluorocyclobutyl)pyridine-2-carbonyl]-4,4-difluoropyrrolidine-2-carboxamide

a) 1-(2-Chloro-6-methylpyridin-3-yl)cyclobutanol

A suspension of molecular sieves (4 Å) and3-bromo-2-chloro-6-methylpyridine (CAN 185017-72-5, 5 g, 24.2 mmol) inTHF (50 mL) was cooled to −15° C. 1.3 M isopropyl magnesium chloridelithium chloride complex solution in THF (19.6 mL, 25.4 mmol) was addedwithin 30 min. Stirring was continued for 1 h at −15° C. Cyclobutanone(1.87 g, 2.00 mL, 26.6 mmol) was slowly added. Stirring was continuedfor 2 h at −15° C. and for further 2 h at 0° C. Water (2.5 mL) wasadded, the mixture was concentrated in vacuo, and poured onto sat.aqueous NH₄Cl solution. The mixture was extracted with EtOAc (2×100 mL).The combined extracts were washed with ice water (50 mL), dried overNa₂SO₄ and concentrated in vacuo. The residue was purified by flashchromatography (silica gel, 140 g, heptane/EtOAc 0-40% in 120 min.) togive the title compound (3.33 g, 70%) as white solid, MS (ESI):m/e=198.1 [MH⁺].

b) 2-Chloro-3-(1-fluorocyclobutyl)-6-methylpyridine

Diethylaminosulfur trifluoride (1.22 g, 1.00 mL, 7.57 mmol) was added toan ice cold solution of 1-(2-chloro-6-methylpyridin-3-yl)cyclobutanol(Example 130 a, 1 g, 5.06 mmol) in dichloromethane (10 mL) keeping thetemperature below 5° C. The reaction mixture was stirred for 30 min. at0° C., poured onto ice water/sat. aqueous Na₂CO₃ solution (35 mL) andextracted with dichloromethane (2×50 mL). The organic layers werecombined, washed with ice water/brine (30 mL), dried over Na₂SO₄ andconcentrated in vacuo. The residue was purified by flash chromatography(silica gel, 50 g, heptane/EtOAc 0-10% in 75 min) to give the titlecompound (939 mg, 93%) as colorless oil, MS (ESI): m/e=200.3 [MH⁺].

c) 2-Chloro-3-(1-fluorocyclobutyl)-6-methylpyridine 1-oxide

3-Chlorobenzoperoxoic acid (173 mg, 1.00 mmol) was added in 2 portionsto a solution of 2-chloro-3-(1-fluorocyclobutyl)-6-methylpyridine(Example 130 b, 100 mg, 501 μmol) in dichloromethane (2 mL). Thereaction mixture was stirred at ambient temperature for 72 h, pouredonto a 10% aqueous Na₂S₂O₃ solution (30 mL) and extracted withdichloromethane (2×40 mL). The combined organic layers were washed withice water/brine (30 mL), dried over Na₂SO₄ and concentrated in vacuo.The residue was dissolved in dichloromethane, washed with sat. NaHCO₃solution (30 mL) and ice water (30 mL), dried over Na₂SO₄ andconcentrated in vacuo to give the title compound (81 mg, 74%) as yellowoil, MS (ESI): m/e=216.3 [MH⁺].

d) (6-Chloro-5-(1-fluorocyclobutyl)pyridin-2-yl)methanol

Trifluoroacetic anhydride (1.27 g, 840 μL, 6.04 mmol) was added underice cooling to a solution of2-chloro-3-(1-fluorocyclobutyl)-6-methylpyridine 1-oxide (Example 130 c,869 mg, 4.03 mmol) in dichloromethane (10.9 mL). The mixture was stirredat ambient temperature for 72 h. Upon ice bath cooling 5 N NaOH solution(1 mL) and afterwards ice water (20 mL) were added. The mixture wasextracted with dichloromethane (2×40 mL). The combined organic layerswere washed with icewater/brine (20 mL), dried over Na₂SO₄ andconcentrated in vacuo. The residue was purified by flash chromatography(silica gel, 50 g, heptane/EtOAc 0-40% in 120 min.) to give the titlecompound (279 mg, 32%) as light yellow oil, MS (ESI): m/e=216.3 [MH⁺].

e) 6-Chloro-5-(1-fluorocyclobutyl)pyridine-2-carboxylic acid

Aqueous phosphate buffer (pH=6.7, 0.7 mL) and TEMPO (2.54 mg, 16.2 μmol)were added to a solution of(6-chloro-5-(1-fluorocyclobutyl)pyridin-2-yl)methanol (Example 130 d, 50mg, 232 μmol) in acetonitrile (1 mL) under an argon atmosphere. Thereaction mixture was warmed to 35° C. A solution of sodium chlorite(52.4 mg, 464 μmol) in 150 μL water and a solution of sodiumhypochlorite (2.66 mg, 2.19 μL, 4.64 μmol) in 100 μL water were addedsimultaneously over a period of 30 min. Stirring was continued at 35° C.for 20 h. Water (40 mL) and 2 N NaOH solution (8 mL) were added. Themixture was poured into an ice cold Na₂SO₃ solution (1.62 Na₂SO₃ g in 30mL water) and stirred for 30 min. at ambient temperature. Under icecooling the mixture was acidified with 25 mL 2 N HCl solution andextracted with a mixture of 100 mL EtOAc and 20 mL THF. The organiclayer was dried over Na₂SO₄, filtered and the solvent concentrated invacuo to give the title compound (66 mg, 90%) as yellow oil, MS(ESI):m/e=230.4 [MH⁺].

f) 6-(Cyclopropylmethoxy)-5-(1-fluorocyclobutyl)pyridine-2-carboxylicacid

Powdered potassium hydroxide (240 mg, 4.28 mmol) was added to a solutionof 6-chloro-5-(1-fluorocyclobutyl)pyridine-2-carboxylic acid (Example130 e, 393 mg, 1.71 mmol) in DMSO (7.86 mL). The mixture was stirred atambient temperature for 15 minutes. Cyclopropylmethanol (136 mg, 153 μL,1.88 mmol) was added and stirring was continued for 5 h at 60° C.Additional cyclopropylmethanol (68 mg, 76 μL, 94 mmol) was added, themixture was stirred for 14 h at ambient temperature, poured ontoice/brine (100 mL) and extracted with TBME (2×100 mL). The aqueous layerwas acidified with 1 N HCl and extracted with EtOAc (2×150 mL). Thecombined organic layers were washed with ice/brine (50 mL), dried overNa₂SO₄ and filtered. The solvent was removed under reduced pressure andthe residue was purified by flash-chromatography (20 g SiO₂,dichloromethane/MeOH 0-3% in 75 min) to give the title compound (65 mg,31%) as colorless oil, MS (ESI) m/e=264.5 [M−H⁻].

g)(2S)-1-[6-(Cyclopropylmethoxy)-5-(1-fluorocyclobutyl)pyridine-2-carbonyl]-4,4-difluoropyrrolidine-2-carboxamide

In analogy to the procedure described in Example 127 e),6-(cyclopropylmethoxy)-5-(1-fluorocyclobutyl)pyridine-2-carboxylic acid(Example 130 f, 20 mg, 49.8 μmol) was reacted with(S)-4,4-difluoropyrrolidine-2-carboxamide hydrochloride (CAN426844-51-1, 11.1 mg, 59.7 μmol) to give the title compound (18 mg, 91%)as off-white solid, MS (EI): m/e=398.4 [MH⁺].

Example 1313-[6-(Cyclopropylmethoxy)-5-(1-hydroxycyclobutyl)pyridine-2-carbonyl]-1,1-dioxo-1,3-thiazolidine-4-carboxamide

In analogy to the procedure described in Example 127 e),6-(cyclopropylmethoxy)-5-(1-hydroxycyclobutyl)pyridine-2-carboxylic acid(CAN 1415899-53-4, 50 mg, 190 μmol) was reacted with1,1-dioxo-1,3-thiazolidine-4-carboxamide hydrochloride (Example 127 d,45.7 mg, 228 μmol) to give the title compound (7 mg, 8%) as colorlessoil, MS (EI): m/e=410.5 [MH⁺].

Example 132(2S)-1-[6-(Cyclopropylmethoxy)-5-(3,3-difluoroazetidin-1-yl)pyridine-2-carbonyl]-4-hydroxy-4-methylpyrrolidine-2-carboxamide

a) (2S)-tert-Butyl2-carbamoyl-4-hydroxy-4-methylpyrrolidine-1-carboxylate

A solution of (2S)-1-ten-butyl 2-methyl4-hydroxy-4-methylpyrrolidine-1,2-dicarboxylate (CAN 1430105-48-8, 50mg, 193 μmol) in a 7 M solution of NH₃ in methanol (551 μL, 3.86 mmol)was stirred at ambient temperature for 72 h. The solvent was removed invacuo to obtain the title compound (48 mg, quant.) as colorless oil, MS(ESI) m/e=145.2 [MH-Boc⁺].

b) (2S)-4-Hydroxy-4-methylpyrrolidine-2-carboxamide hydrochloride

A solution of (2S)-tert-butyl2-carbamoyl-4-hydroxy-4-methylpyrrolidine-1-carboxylate (Example 132 a,46 mg, 188 μmol) in a solution of 4 M HCl in dioxane (942 μL, 3.8 mmol)was stirred at ambient temperature for 5 h. The solvent was removed invacuo to give the title compound (36 mg, quant.) as light brown solid,MS (ESI) m/e=145.2 [MH⁺].

c)(2S)-1-[6-(Cyclopropylmethoxy)-5-(3,3-difluoroazetidin-1-yl)pyridine-2-carbonyl]-4-hydroxy-4-methylpyrrolidine-2-carboxamide

In analogy to the procedure described in Example 47 b),6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylicacid (Example 1 b, 20 mg, 70.4 μmol) was reacted with(2S)-4-hydroxy-4-methylpyrrolidine-2-carboxamide hydrochloride (Example132 b, 15.3 mg, 84.4 μmol) to obtain the title compound (22 mg, 76%) asoff-white solid; MS (EI): m/e=411.5 [MH⁺].

Example 1333-[6-(Cyclopropylmethoxy)-5-(1-fluorocyclobutyl)pyridine-2-carbonyl]-1,1-dioxo-1,3-thiazolidine-4-carboxamide

In analogy to the procedure described in Example 127 e),6-(cyclopropylmethoxy)-5-(1-fluorocyclobutyl)pyridine-2-carboxylic acid(Example 130 f) was reacted with1,1-dioxo-1,3-thiazolidine-4-carboxamide hydrochloride (Example 127 d)to give the title compound as yellow oil, MS (EI): m/e=412.13 [MH⁺].

Example 134(2S)-1-[6-(Cyclopropylmethoxy)-5-(3-fluorooxetan-3-yl)pyridine-2-carbonyl]-4,4-difluoropyrrolidine-2-carboxamide

a) 3-(2-Chloro-6-methylpyridin-3-yl)oxetan-3-ol

In analogy to the procedure described in Example 130 a),3-bromo-2-chloro-6-methylpyridine (CAN 185017-72-5, 5 g, 24.2 mmol) wasreacted with oxetan-3-one (CAN 6704-31-0, 1.75 g, 1.42 mL, 24.2 mmol) togive the title compound (3.42 g, 71%) as off-white solid, MS (ESI):m/e=200.5 [MH⁺].

b) 2-Chloro-3-(3-fluorooxetan-3-yl)-6-methylpyridine

In analogy to the procedure described in Example 130 b),3-(2-chloro-6-methylpyridin-3-yl)oxetan-3-ol (Example 134 a, 1.5 g, 7.51mmol) was reacted with diethylaminosulfur trifluoride to obtain thetitle compound (850 mg, 56%) as colorless liquid, MS (ESI): m/e=202.1[MH⁺].

c) 2-Chloro-3-(3-fluorooxetan-3-yl)-6-methylpyridine 1-oxide

In analogy to the procedure described in Example 130 c),2-chloro-3-(3-fluorooxetan-3-yl)-6-methylpyridine (Example 134 b, 850mg, 4.22 mmol) was oxidized to give the title compound (875 mg, 95%) aslight brown solid, MS (ESI): m/e=218.4 [MH⁺].

d) (6-Chloro-5-(3-fluorooxetan-3-yl)pyridin-2-yl)methanol

In analogy to the procedure described in Example 130 d),2-chloro-3-(3-fluorooxetan-3-yl)-6-methylpyridine 1-oxide (Example 134c, 870 mg, 4 mmol) was rearranged to give the title compound (154 mg,18%) as colorless liquid, MS (ESI): m/e=218.4 [MH⁺].

e) 6-Chloro-5-(3-fluorooxetan-3-yl)pyridine-2-carboxylic acid

In analogy to the procedure described in Example 130 e),(6-chloro-5-(3-fluorooxetan-3-yl)pyridin-2-yl)methanol (Example 134 d,154 mg, 708 μmol) was oxidized to obtain the title compound (66 mg, 40%)as off-white solid, MS(ESI): m/e=232.1 [MH⁺].

f) 6-(Cyclopropylmethoxy)-5-(3-fluorooxetan-3-yl)pyridine-2-carboxylicacid

6-Chloro-5-(3-fluorooxetan-3-yl)pyridine-2-carboxylic acid (Example 134e, 44 mg, 190 μmol) and cyclopropylmethanol (CAN 2516-33-8, 17.8 mg,20.0 μL, 247 μmol) were dissolved in DMF (1.32 mL). A solution of sodium2-methylpropan-2-olate (42.0 mg, 437 μmol) in THF (800 μL) was added andthe mixture was heated to 50° C. for 3 h and for additional 3 h to 70°C. After cooling to ambient temperature, the reaction mixture was pouredonto ice/0.1 N HCl (25 mL) and extracted with EtOAc (2×25 mL). Thecombined extracts were washed with ice/brine (20 mL), dried over Na₂SO₄,filtered and evaporated to dryness. The residue was purified by thinlayer chromatography (2 mm SiO₂, dichloromethane/MeOH 19:1, elution withEtOAc) to give the title compound (11 mg, 22 mg) as colorless oil, MS(ESI) m/e=268.2 [MH⁺].

g)(2S)-1-[6-(Cyclopropylmethoxy)-5-(3-fluorooxetan-3-yl)pyridine-2-carbonyl]-4,4-difluoropyrrolidine-2-carboxamide

In analogy to the procedure described in Example 127 e),6-(cyclopropylmethoxy)-5-(3-fluorooxetan-3-yl)pyridine-2-carboxylic acid(Example 134 f, 25 mg, 93.5 μmol) was reacted with(S)-4,4-difluoropyrrolidine-2-carboxamide hydrochloride (CAN426844-51-1, 20.9 mg, 112 μmol) to give the title compound (20 mg, 54%)as colorless oil, MS (EI): m/e=400.2 [MH⁺].

Example 1355-[6-(Cyclopropylmethoxy)-5-(3,3-difluoroazetidin-1-yl)pyridine-2-carbonyl]-5-azaspiro[2.4]heptane-6-carboxamide

a) tert-Butyl 6-carbamoyl-5-azaspiro[2.4]heptane-5-carboxylate

In analogy to the procedure described in Example 127 c),5-(tert-butoxycarbonyl)-5-azaspiro[2.4]heptane-6-carboxylic acid (CAN1454843-77-6, 112 mg, 464 μmol) was condensed with ammonia to give thetitle compound (87 mg, 78%) as colorless liquid, MS (EI): m/e=240.0[M⁺].

b) 5-Azaspiro[2.4]heptane-6-carboxamide hydrochloride

In analogy to the procedure described in Example 132 b), tert-butyl6-carbamoyl-5-azaspiro[2.4]heptane-5-carboxylate (Example 135 a, 65 mg,270 μmol) was deprotected to give the title compound (55 mg, quant.) aslight yellow solid, LC-MS (UV peak area/ESI) 100%, 141.1023 [MH⁺].

c)5-[6-(Cyclopropylmethoxy)-5-(3,3-difluoroazetidin-1-yl)pyridine-2-carbonyl]-5-azaspiro[2.4]heptane-6-carboxamide

In analogy to the procedure described in Example 127 e),6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylicacid (Example 1 b, 18.6 mg, 106 μmol) was reacted with5-azaspiro[2.4]heptane-6-carboxamide hydrochloride (Example 135 b, 18.6mg, 106 μmol) to obtain the title compound (16 mg, 56%) as colorlessliquid, MS (EI): m/e=407.3 [MH⁺].

Example 136[6-(Cyclopropylmethoxy)-5-(3,3-difluoroazetidin-1-yl)pyridin-2-yl]-[3-(2,2,2-trifluoro-1-hydroxyethyl)pyrrolidin-1-yl]methanone

In analogy to the procedure described in Example 127 e),6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylicacid (Example 1 b, 20 mg, 70.4 μmol) was reacted with2,2,2-trifluoro-1-(pyrrolidin-3-yl)ethanol hydrochloride (CAN ofcorresponding free base: 943906-23-8, 14.5 mg, 70.4 μmol) to obtain thetitle compound (14 mg, 46%) as colorless liquid, MS (EI): m/e=436.4[MH⁺].

Example 137[6-(Cyclopropylmethoxy)-5-(3,3-difluoroazetidin-1-yl)pyridin-2-yl]-[3-(hydroxymethyl)-3-(trifluoromethyl)pyrrolidin-1-yl]methanone

In analogy to the procedure described in Example 127 e),6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylicacid (Example 1 b, 20 mg, 70.4 μmol) was reacted with(3-(trifluoromethyl)pyrrolidin-3-yl)methanol hydrochloride (CAN1260812-78-9, 17.4 mg, 84.4 μmol) to obtain the title compound (11 mg,36%) as colorless liquid, MS (EI): m/e=436.4 [MH⁺].

Example 138[6-(Cyclopropylmethoxy)-5-(3,3-difluoroazetidin-1-yl)pyridin-2-yl]-[3-hydroxy-3-(trifluoromethyl)pyrrolidin-1-yl]methanone

In analogy to the procedure described in Example 127 e),6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylicacid (Example 1 b, 40 mg, 141 μmol) was reacted with3-(trifluoromethyl)pyrrolidin-3-ol hydrochloride (CAN 1334147-81-7, 32.4mg, 169 μmol) to obtain the title compound (28 mg, 47%) as off-whitesolid, MS (EI): m/e=422.3 [MH⁺].

Example 139[6-(Cyclopropylmethoxy)-5-(3,3-difluoroazetidin-1-yl)pyridin-2-yl]-[3-hydroxy-3-(trifluoromethyl)azetidin-1-yl]methanone

In analogy to the procedure described in Example 127 e),6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylicacid (Example 1 b, 40 mg, 141 μmol) was reacted with3-(trifluoromethyl)azetidin-3-ol hydrochloride (CAN 848192-96-1, 30.0mg, 169 μmol) to obtain the title compound (32 mg, 56%) as off-whitesolid, MS (EI): m/e=408.3 [MH⁺].

Example 140(+)-(2S)-1-[6-(Cyclopropylmethoxy)-5-(3,3-difluoroazetidin-1-yl)pyridine-2-carbonyl]-4-hydroxy-4-methylpyrrolidine-2-carboxamide

In analogy to the procedure described in Example 127 e),6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylicacid (Example 1 b, 50 mg, 176 μmol) was reacted with(2S)-4-hydroxy-4-methylpyrrolidine-2-carboxamide hydrochloride (Example132 b, 39.7 mg, 176 μmol) and purified by chiral HPLC to obtain thetitle compound (8 mg, 10%) as white solid, LC-MS (UV peak area, ESI)93%, 411.1854 [MH⁺].

Example 141[5-Cyclopropyl-6-(cyclopropylmethoxy)pyridin-2-yl]-[3-(2,2,2-trifluoro-1-hydroxyethyl)pyrrolidin-1-yl]methanone

In analogy to the procedure described in Example 127 e),5-cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid (Example 3c, 20 mg, 85.7 μmol) was reacted with2,2,2-trifluoro-1-(pyrrolidin-3-yl)ethanol hydrochloride (CAN ofcorresponding free base: 943906-23-8, 21.2 mg, 103 μmol) to obtain thetitle compound (16 mg, 49%) as colorless liquid, MS (EI): m/e=385.3[MH⁺].

Example 142[5-Cyclopropyl-6-(cyclopropylmethoxy)pyridin-2-yl]-[3-(hydroxymethyl)-3-(trifluoromethyl)pyrrolidin-1-yl]methanone

In analogy to the procedure described in Example 127 e),5-cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid (Example 3c, 20 mg, 85.7 μmol) was reacted with(3-(trifluoromethyl)pyrrolidin-3-yl)methanol hydrochloride (CAN1260812-78-9, 21.2 mg, 103 μmol) to obtain the title compound (12 mg,36%) as colorless liquid, MS (EI): m/e=385.3 [MH⁺].

Example 143[5-Cyclopropyl-6-(cyclopropylmethoxy)pyridin-2-yl]-[3-hydroxy-3-(trifluoromethyl)pyrrolidin-1-yl]methanone

In analogy to the procedure described in Example 127 e),5-cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid (Example 3c, 20 mg, 85.7 μmol) was reacted with 3-(trifluoromethyl)pyrrolidin-3-olhydrochloride (CAN 1334147-81-7, 19.7 mg, 103 μmol) to obtain the titlecompound (15 mg, 47%) as colorless liquid, MS (EI): m/e=371.3 [MH⁺].

Example 144[5-Cyclopropyl-6-(cyclopropylmethoxy)pyridin-2-yl]-[3-hydroxy-3-(trifluoromethyl)azetidin-1-yl]methanone

In analogy to the procedure described in Example 127 e),5-cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid (Example 3c, 20 mg, 85.7 μmol) was reacted with 3-(trifluoromethyl)azetidin-3-olhydrochloride (CAN 848192-96-1, 18.3 mg, 103 μmol) to obtain the titlecompound (7 mg, 23%) as colorless oil, MS (EI): m/e=357.3 [MH⁺].

Example 145(6S)-5-[6-(Cyclopropylmethoxy)-5-(3,3-difluoroazetidin-1-yl)pyridine-2-carbonyl]-5-azaspiro[2.4]heptane-6-carboxamide

In analogy to the procedure described in Example 127 e),6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylicacid (Example 1 b, 50 mg, 176 μmol) was reacted with5-azaspiro[2.4]heptane-6-carboxamide hydrochloride (Example 135 b, 37.3mg, 211 μmol) and purified by chiral HPLC to obtain the title compound(12 mg, 17%) as colorless oil, MS (EI): m/e=407.3 [MH⁺].

Example 146[(3aR,6aS)-1,3,3a,4,6,6a-Hexahydrofuro[3,4-c]pyrrol-5-yl]-[6-(cyclopropylmethoxy)-5-(3,3-difluoroazetidin-1-yl)pyridin-2-yl]methanone

In analogy to the procedure described in Example 127 e),6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylicacid (Example 1 b, 30 mg, 106 μmol) was reacted with(3aR,6aS)-hexahydro-1H-furo[3,4-c]pyrrole hydrochloride (CAN 57710-36-8,15.8 mg, 106 μmol) to obtain the title compound (22 mg, 55%) as whitesolid, MS (EI): m/e=380.3 [MH⁺].

Example 147(2S)-1-[5-(3,3-Difluoroazetidin-1-yl)-6-(2-fluoroethoxyl)pyridine-2-carbonyl]-4,4-difluoro-pyrrolidine-2-carboxamide

a) Methyl 5-bromo-6-(2-fluoroethoxyl)pyridine-2-carboxylate

Lithium 2-methylpropan-2-olate (4.17 mL, 9.18 mmol) was added within 30minutes at ambient temperature to a solution of methyl5-bromo-6-chloro-pyridine-2-carboxylate (CAN 1214353-79-3, 1 g, 3.99mmol) and 2-fluoroethanol (CAN 371-62-0, 332 mg, 300 μL, 5.19 mmol) inDMF (6.67 mL). The reaction mixture was heated to 70° C. and stirred for6 h. After cooling to ambient temperature, water (5 mL) and 2N HCl (5mL) were added. The mixture was poured onto ice/brine (50 mL) andextracted with EtOAc (2×50 mL). The combined extracts were washed withice/brine (50 mL), dried over Na₂SO₄, filtered and evaporated todryness. The crude product was purified by flash-chromatography (50 gSiO₂, heptane/0-30% EtOAc in 120 min.) to give the title compound (132mg, 12%) as light brown solid, MS (ESI) m/e=278.0 [MH⁺].

b) Methyl5-(3,3-difluoroazetidin-1-yl)-6-(2-fluoroethoxyl)pyridine-2-carboxylate

In analogy to the procedure described in Example 1 a), methyl5-bromo-6-(2-fluoroethoxyl)pyridine-2-carboxylate (Example 147 a, 130mg, 467 μmol) was reacted with 3,3-difluoroazetidine hydrochloride (CAN288315-03-7, 66.6 mg, 514 μmol) in the presence of palladium (II)acetate, 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl and cesiumcarbonate to give the title compound (73 mg, 54%) as light yellow solid,MS (ESI) m/e=291.1 [MH⁺].

c)5-(3,3-Difluoroazetidin-1-yl)-6-(2-fluoroethoxyl)pyridine-2-carboxylicacid

A solution of methyl5-(3,3-difluoroazetidin-1-yl)-6-(2-fluoroethoxyl)pyridine-2-carboxylate(Example 147 b, 73 mg, 252 μmol) and lithium hydroxide hydrate (12.7 mg,302 μmol) in tetrahydrofuran (500 μL) and water (50.0 μL) was stirredfor 12 h at ambient temperature. The reaction mixture was poured ontoice/0.1 N HCl (25 mL) and extracted with EtOAc (2×25 mL). The combinedextracts were washed with ice/brine (25 mL), dried over Na₂SO₄, filteredand evaporated to dryness to give the target compound (69 mg, quant.) asoff-white solid, MS (ESI) m/e=277.1 [MH⁺].

d)(2S)-1-[5-(3,3-Difluoroazetidin-1-yl)-6-(2-fluoroethoxy)pyridine-2-carbonyl]-4,4-difluoro-pyrrolidine-2-carboxamide

In analogy to the procedure described in Example 127 e),5-(3,3-difluoroazetidin-1-yl)-6-(2-fluoroethoxyl)pyridine-2-carboxylicacid (Example 147 c, 25 mg, 90.5 μmol) was reacted with(S)-4,4-difluoropyrrolidine-2-carboxamide hydrochloride (CAN426844-51-1, 20.3 mg, 109 μmol) to obtain the title compound (16 mg,43%) as off-white solid, MS (ESI): m/e=409.1304 [MH⁺].

Example 148[6-(Cyclopropylmethoxy)-5-(3,3-difluoroazetidin-1-yl)-2-pyridyl]-[3-fluoro-3-(hydroxymethyl)azetidin-1-yl]methanone

In analogy to the procedure described in Example 127 e),6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylicacid (Example 1 b, 20 mg, 70.4 μmol) was reacted with(3-fluoroazetidin-3-yl)methanol (CAN 1268520-93-9, 8.87 mg, 84.4 μmol)to obtain the title compound (11 mg, 42%) as colorless liquid, MS (ESI):m/e=372.2 [MH⁺].

Example 149[6-(Cyclopropylmethoxy)-5-(3,3-difluoroazetidin-1-yl)-2-pyridyl]-(3-fluoro-3-methyl-azetidin-1-yl)methanone

In analogy to the procedure described in Example 127 e),6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylicacid (Example 1 b, 20 mg, 70.4 μmol) was reacted with3-fluoro-3-methylazetidine hydrochloride (CAN 1427379-42-7, 10.6 mg,84.4 μmol) to obtain the title compound (6 mg, 24%) as off-white solid,MS (ESI): m/e=356.2 [MH⁺].

Example 150(3-Cyclopropyl-3-fluoroazetidin-1-yl)-[6-(cyclopropylmethoxy)-5-(3,3-difluoroazetidin-1-yl)pyridin-2-yl]methanone

In analogy to the procedure described in Example 127 e),6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylicacid (Example 1 b, 20 mg, 70.4 μmol) was reacted with3-cyclopropyl-3-fluoroazetidine hydrochloride (CAN 936548-77-5, 12.8 mg,84.4 μmol) to obtain the title compound (8 mg, 30%) as colorless liquid,MS (ESI): m/e=382.3 [MH⁺].

Example 151(−)-5-[6-(Cyclopropylmethoxy)-5-(3,3-difluoroazetidin-1-yl)pyridine-2-carbonyl]-5-azaspiro[2.4]heptane-4-carboxamide

a) tert-Butyl 4-formyl-5-azaspiro[2.4]heptane-5-carboxylate andtert-butyl 4-ethyl-2-formyl-4-methyl-pyrrolidine-1-carboxylate

A solution of s-butyllithium in cyclohexane (1.13 mL, 1.58 mmol) wasadded at −30° C. within 5 min. to a solution of tert-butyl5-azaspiro[2.4]heptane-5-carboxylate (CAN 1026796-26-8, 240 mg, 1.22mmol) in THF (9.6 mL). After stirring for 5 min. DMF (177 mg, 188 μL,2.43 mmol) was added and stirring at −30° C. was continued for 10 min.The mixture was allowed to warm to ambient temperature and stirring wascontinued for 15 min. The reaction mixture was poured onto ice/saturatedNH₄Cl-solution (25 mL) and extracted with EtOAc (2×25 mL). The combinedextracts were washed with ice/brine (25 mL), dried over Na₂SO₄, filteredand evaporated to dryness. The crude product was purified by prep. TLC(2 mm SiO₂.heptan/EtOAc 4:1, elution with EtOAc) to give the titlecompounds (145 mg, 53%) as colorless liquid, MS (ESI) m/e=126.1[MH-Boc⁺].

b) 5-tert-Butoxycarbonyl-5-azaspiro[2.4]heptane-4-carboxylic acid and1-tert-butoxycarbonyl-4-ethyl-4-methyl-pyrrolidine-2-carboxylic acid

A mixture of tert-butyl 4-formyl-5-azaspiro[2.4]heptane-5-carboxylateand tert-butyl 4-ethyl-2-formyl-4-methyl-pyrrolidine-1-carboxylate(Example 151 a, 142 mg, 630 μmol) was dissolved in t-BuOH (3.69 mL) and2-methyl-2-butene (1.99 mL). A solution of sodium chlorite (114 mg, 1.26mmol) and sodium dihydrogen phosphate dihydrate (151 mg, 1.26 mmol) inwater (568 μL) was added. The mixture was stirred at ambient temperaturefor 90 minutes and concentrated in vacuo. The residue was dissolved inwater (10 mL). The pH was adjusted to 3-4 by dropwise addition of 2 NHCl. The mixture was extracted with EtOAc (2×25 mL) and the combinedextracts were washed with ice/brine (25 mL), dried over Na₂SO₄ andevaporated to dryness. The crude product was poured onto ice/brine/1 MNaOH (20 mL) and extracted with tBuOMe (2×25 mL). The aqueous layer wasacidified with icewater/1M HCl (20 mL) and extracted with EtOAc (2×25mL). The combined extracts were washed with ice/brine (25 mL) dried overNa₂SO₄, filtered and evaporated to dryness to obtain the title compounds(155 mg, quant.) as colorless oil.

c) tert-Butyl 4-carbamoyl-5-azaspiro[2.4]heptane-5-carboxylate andtert-butyl 2-carbamoyl-4-ethyl-4-methyl-pyrrolidine-1-carboxylate

In analogy to the procedure described in Example 127 c), a mixture of5-tert-butoxycarbonyl-5-azaspiro[2.4]heptane-4-carboxylic acid and1-tert-butoxycarbonyl-4-ethyl-4-methyl-pyrrolidine-2-carboxylic acid(Example 151 b, 152 mg, 630 μmol) was condensed with ammonia to give thetitle compounds (118 mg, 78%) as off-white amorphous, MS (EI): m/e=141.1[MH-Boc⁺].

d) 5-Azaspiro[2.4]heptane-4-carboxamide hydrochloride and5-azaspiro[2.4]heptane-6-carboxamide hydrochloride

A mixture of tert-butyl 4-carbamoyl-5-azaspiro[2.4]heptane-5-carboxylateand tert-butyl 2-carbamoyl-4-ethyl-4-methyl-pyrrolidine-1-carboxylate(Example 151 c, 115 mg, 479 μmol) was dissolved in a 4 M solution of HClin dioxane (2.39 mL, 9.55 mmol) and stirred for 4 h at ambienttemperature. Removal of the solvent in vacuo gave the title compounds(115 mg, quant.) as light yellow oil.

e)(−)-5-[6-(Cyclopropylmethoxy)-5-(3,3-difluoroazetidin-1-yl)pyridine-2-carbonyl]-5-azaspiro[2.4]heptane-4-carboxamide

In analogy to the procedure described in Example 127 e),6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylicacid (Example 1 b, 80 mg, 281 μmol) was reacted with a mixture of5-azaspiro[2.4]heptane-4-carboxamide hydrochloride and5-azaspiro[2.4]heptane-6-carboxamide hydrochloride (Example 151 d, 59.7mg, 338 μmol) to obtain the title compound after preparative chiral HPLC(10 mg, 9%) as off-white solid, MS (ESI): m/e=407.3 [MH⁺].

Example 152(+)-5-[6-(Cyclopropylmethoxy)-5-(3,3-difluoroazetidin-1-yl)pyridine-2-carbonyl]-5-azaspiro[2.4]heptane-4-carboxamide

In analogy to the procedure described in Example 127 e),6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylicacid (Example 1 b, 80 mg, 281 μmol) was reacted with a mixture of5-azaspiro[2.4]heptane-4-carboxamide hydrochloride and5-azaspiro[2.4]heptane-6-carboxamide hydrochloride (Example 151 d, 59.7mg, 338 μmol) to obtain the title compound after preparative chiral HPLC(22 mg, 19%) as off-white solid, MS (ESI): m/e=407.3 [MH⁺].

Example 153 Pharmacological Tests

The following tests were carried out in order to determine the activityof the compounds of formula (I).

Radioligand Binding Assay

The affinity of the compounds of the invention for cannabinoid CB1receptors was determined using recommended amounts of membranepreparations (PerkinElmer) of human embryonic kidney (HEK) cellsexpressing the human CNR1 or CNR2 receptors in conjunction with 1.5 or2.6 nM [3H]-CP-55,940 (Perkin Elmer) as radioligand, respectively.Binding was performed in binding buffer (50 mM Tris, 5 mM MgCl2, 2.5 mMEDTA, and 0.5% (wt/vol) fatty acid free BSA, pH 7.4 for CB1 receptor and50 mM Tris, 5 mM MgCl₂, 2.5 mM EGTA, and 0.1% (wt/vol) fatty acid freeBSA, pH 7.4 for CB2 receptor) in a total volume of 0.2 ml for 1 h at 30°C. shaking. The reaction was terminated by rapid filtration throughmicrofiltration plates coated with 0.5% polyethylenimine (UniFilter GF/Bfilter plate; Packard). Bound radioactivity was analyzed for Ki usingnonlinear regression analysis (Activity Base, ID Business Solution,Limited), with the Kd values for [3H]CP55,940 determined from saturationexperiments. The compounds of formula (I) show an excellent affinity forthe CB2 receptor with affinities below 10 μM, more particularly of 1 nMto 3 μM and most particularly of 1 nM to 100 nM.

cAMP Assay

CHO cells expressing human CB1 or CB2 receptors are seeded 17-24 hoursprior to the experiment 50.000 cells per well in a black 96 well platewith flat clear bottom (Corning Costar #3904) in DMEM (Invitrogen No.31331), 1×HT supplement, with 10% fetal calf serum and incubated at 5%CO₂ and 37° C. in a humidified incubator. The growth medium wasexchanged with Krebs Ringer Bicarbonate buffer with 1 mM IBMX andincubated at 30° C. for 30 min. Compounds were added to a final assayvolume of 100 μl and incubated for 30 min at 30° C. Using thecAMP-Nano-TRF detection kit the assay (Roche Diagnostics) was stopped bythe addition of 50 μl lysis reagent (Tris, NaCl, 1.5% Triton X100, 2.5%NP40, 10% NaN₃) and 50 μl detection solutions (20 μM mAb Alexa700-cAMP1:1, and 48 μM Ruthenium-2-AHA-cAMP) and shaken for 2 h at roomtemperature. The time-resolved energy transfer is measured by a TRFreader (Evotec Technologies GmbH), equipped with a ND:YAG laser asexcitation source. The plate is measured twice with the excitation at355 nm and at the emission with a delay of 100 ns and a gate of 100 ns,total exposure time 10 s at 730 (bandwidth 30 nm) or 645 nm (bandwidth75 nm), respectively. The FRET signal is calculated as follows:FRET=T730-Alexa730-P(T645-B645) with P=Ru730-B730/Ru645-B645, where T730is the test well measured at 730 nM, T645 is the test well measured at645 nm, B730 and B645 are the buffer controls at 730 nm and 645 nm,respectively. cAMP content is determined from the function of a standardcurve spanning from 10 μM to 0.13 nM cAMP.

EC₅₀ values were determined using Activity Base analysis (ID BusinessSolution, Limited). The EC₅₀ values for a wide range of cannabinoidagonists generated from this assay were in agreement with the valuespublished in the scientific literature.

The compounds of the invention are CB2 agonists with EC₅₀ below 0.5 μMand selectivity versus CB1 in the corresponding assay of at least 10fold. Particular compound of the invention are CB2 agonists with EC₅₀below 0.05 μM and selectivity versus CB1 in the corresponding assay ofat least 100 fold.

For example, the following compounds showed the following human EC₅₀values in the functional cAMP assay described above:

human human CB2 EC50 CB1 EC50 Example [μM] [μM] 1 0.0046 >10 20.2969 >10 3 0.0072 >10 4 0.0085 >10 5 0.0008 0.2681 6 0.1056 >10 70.0006 0.2923 8 0.0126 >10 9 0.0038 >10 10 0.6615 >10 11 0.3643 >10 120.1335 >10 13 0.1188 >10 14 0.0073 >10 15 0.2488 >10 16 0.008 >10 170.0052 >10 18 0.0006 >10 19 0.8556 >10 20 0.0053 >10 21 0.0028 >10 220.025 >10 23 0.0058 >10 24 0.3397 >10 25 0.037 >10 26 0.3055 >10 270.7736 >10 28 0.4143 >10 29 0.4138 >10 30 0.0345 >10 31 0.0821 >10 320.2559 >10 33 0.0554 >10 34 0.0911 >10 35 0.1834 >10 36 0.2257 >10 370.3644 >10 38 0.2124 >10 39 0.1422 >10 40 0.0818 >10 41 0.9659 >10 420.009 >10 43 0.0349 >10 44 0.0031 0.408 45 0.0068 >10 46 0.3596 >10 470.1131 >10 48 0.108 >10 49 0.1386 >10 50 0.2374 >10 51 0.7888 >10 520.6454 >10 53 0.0037 >10 54 0.4621 >10 55 0.0554 >10 56 0.0369 >10 570.0018 >10 58 0.5937 >10 59 0.0142 >10 60 0.003075 >10 61 0.3912 >10 620.0091 >10 63 0.198 >10 64 0.0405 >10 65 0.1001 >10 66 0.0056 >10 670.3676 >10 68 0.0027 >10 69 1.0416 >10 70 0.1037 >10 71 0.4435 >10 720.664 >10 73 0.6365 >10 74 0.0115 >10 75 0.0162 >10 76 0.0002 0.1673 770.1942 >10 78 0.0012 >10 79 0.5188 >10 80 0.3415 >10 81 0.6525 >10 820.3556 >10 83 0.7595 >10 84 0.0189 >10 85 0.0854 >10 86 0.0727 >10 870.768 >10 88 0.1802 >10 89 0.3184 >10 90 0.0148 >10 91 0.8929 >10 920.1008 >10 93 0.3269 >10 94 0.0802 >10 95 0.0104 >10 96 0.1034 >10 970.0723 >10 98 0.0066 >10 99 0.3052 >10 100 0.0208 >10 101 0.0049 >10 1020.1806 >10 103 0.0048 >10 104 0.0074 >10 105 0.218 >10 106 0.1229 >10107 0.7574 >10 108 0.1556 >10 109 0.3604 >10 110 0.3855 >10 111 0.0082.7772 112 0.0198 >10 113 0.212 >10 114 0.4732 >10 115 0.0072 >10 1160.6715 >10 117 0.4851 >10 118 0.0132 >10 119 0.5991 >10 120 0.042 >10121 0.112 >10 122 0.05 >10 123 0.0584 >10 124 0.0526 >10 125 0.0095 >10126 0.04 >10 127 0.0034 >10 128 0.0302 >10 129 0.0758 >10 130 0.0023 >10131 0.0625 >10 132 0.0301 >10 133 0.0102 >10 134 0.0522 >10 1350.0156 >10 136 0.0329 >10 137 0.0538 >10 138 0.0835 >10 139 0.042 >10140 0.0406 >10 141 0.2619 >10 142 0.0263 >10 143 0.0878 >10 1440.073 >10 145 0.3562 >10 146 0.1673 >10 147 1.167 >10 148 0.451 >10 1490.079 >10 150 0.008 >10 151 0.818 >10 152 0.338 >10

Example A

Film coated tablets containing the following ingredients can bemanufactured in a conventional manner:

Ingredients Per tablet Kernel: Compound of formula (I) 10.0 mg 200.0 mgMicrocrystalline cellulose 23.5 mg 43.5 mg Lactose hydrous 60.0 mg 70.0mg Povidone K30 12.5 mg 15.0 mg Sodium starch glycolate 12.5 mg 17.0 mgMagnesium stearate 1.5 mg 4.5 mg (Kernel Weight) 120.0 mg 350.0 mg FilmCoat: Hydroxypropyl methyl cellulose 3.5 mg 7.0 mg Polyethylene glycol6000 0.8 mg 1.6 mg Talc 1.3 mg 2.6 mg Iron oxide (yellow) 0.8 mg 1.6 mgTitan dioxide 0.8 mg 1.6 mg

The active ingredient is sieved and mixed with microcrystallinecellulose and the mixture is granulated with a solution ofpolyvinylpyrrolidone in water. The granulate is then mixed with sodiumstarch glycolate and magnesium stearate and compressed to yield kernelsof 120 or 350 mg respectively. The kernels are lacquered with an aq.solution/suspension of the above mentioned film coat.

Example B

Capsules containing the following ingredients can be manufactured in aconventional manner:

Ingredients Per capsule Compound of formula (I) 25.0 mg Lactose 150.0 mgMaize starch 20.0 mg Talc 5.0 mg

The components are sieved and mixed and filled into capsules of size 2.

Example C

Injection solutions can have the following composition:

Compound of formula (I) 3.0 mg Polyethylene glycol 400 150.0 mg Aceticacid q.s. ad pH 5.0 Water for injection solutions ad 1.0 ml

The active ingredient is dissolved in a mixture of Polyethylene glycol400 and water for injection (part). The pH is adjusted to 5.0 byaddition of acetic acid. The volume is adjusted to 1.0 ml by addition ofthe residual amount of water. The solution is filtered, filled intovials using an appropriate overage and sterilized.

The invention claimed is:
 1. A compound of formula (I)

wherein R¹ is cycloalkylalkoxy, halophenyl, tetrahydrofuranylalkoxy,halophenylalkyl, haloalkyloxy, alkylsulfonyl, tetrahydropyranylalkoxy orhalogen; R² is alkyl, pyrrolidinyl, cycloalkyl, haloazetidinyl,haloalkyl, cycloalkylalkoxy, haloalkyloxy, halocycloalkyl,hydroxycycloalkyl or halooxetanyl; one of R³ and R⁴ is alkyl,cycloalkyl, haloalkyl or hydroxyalkyl and the other one is alkyl,alkyloxyalkyl, (haloazetidinyl)(cycloalkyloxy)pyridinylcarbonyloxyalkyl,haloalkylcycloalkyl, hydroxyalkyl, phenylalkyl, alkoxycarbonylalkyl,carboxyalkyl, alkylaminocarbonylalkyl,(alkyloxadiazolyl)(cycloalkylalkyl)alkyl,(alkyloxadiazolyl)(cycloalkyl)alkyl, pyridazinylalkyl,aminocarbonylalkyl, alkyloxadiazolylalkyl, alkyltetrazolylalkyl, formyl,phenyl, dialkylpyrazolyl, alkylcarbonylpiperidinyl or cycloalkylalkyl;or R³ and R⁴ together with the nitrogen atom to which they are attachedform heterocyclyl or substituted heterocyclyl; wherein heterocyclyl is6-oxa-1-aza-spiro[3.3]heptyl, oxazolidinyl, morpholinyl, pyrrolidinyl,piperazinyl, 2-oxa-5-aza-spiro[3.4]octyl, piperidinyl,6-aza-bicyclo[3.2.1.]octyl, imidazolidinyl, 4-aza-spiro[2.4]heptyl,2-aza-bicyclo[2.2.1]heptyl, 2-thia-5-aza-bicyclo[2.2.1]heptyl,2,5-diazabicyclo[2.2.1]heptyl, 2-oxa-5-aza-bicyclo[2.2.1]heptyl,hexahydro-furo[2,3-c]pyrrolyl, 2-thia-6-aza-spiro[3.3]heptyl,1,8-diaza-spiro[4.5]decyl, 1-oxa-7-aza-spiro[4.4]nonyl,5-oxa-2-aza-spiro[3.4]octyl, 8-oxa-3-aza-bicyclo[3.2.1]octyl,3-oxa-8-aza-bicyclo[3.2.1]octyl, thiomorpholinyl, thiazolidinyl,5-aza-spiro[3.4]octyl, azetidinyl, 5-aza-spiro[2.4]heptyl,3-aza-bicyclo[3.1.0]hexyl or 5-aza-spiro[2.4]heptyl,1,3,3a,4,6,6a-hexahydrofuro[3,4-c]pyrrolyl; and wherein substitutedheterocyclyl is heterocyclyl substituted with one to four substituentsindependently selected from alkyl, oxo, hydroxyl, carboxyl,alkylcarbonylamino, alkyloxyalkyl, hydroxyalkyl, aminocarbonyl, halogen,phenylalkyl, phenyl, alkoxycarbonyl, cycloalkylalkyl,phenylalkoxycarbonyl, cycloalkyl, halohydroxyalkyl and haloalkyl;provided that R³ and R⁴ together with the nitrogen atom to which theyare attached don't form unsubstituted piperidinyl, unsubstitutedthiomorpholinyl or hydroxyalkylpyrrolidinyl; or a pharmaceuticallyacceptable salt or ester thereof.
 2. A compound according to claim 1,wherein R¹ is cycloalkylalkoxy, tetrahydrofuranylalkoxy, alkylsulfonylor halophenylalkyl.
 3. A compound according to claim 1, wherein R¹ iscyclopropylmethoxy, tetrahydrofuranylmethoxy, isobutylsulfonyl orfluorophenylmethyl.
 4. A compound according to claim 1, wherein R² ishaloazetidinyl, cycloalkyl or halocycloalkyl.
 5. A compound according toclaim 1, wherein R² is difluoroazetidinyl, cyclopropyl orfluorocyclobutyl.
 6. A compound according to claim 1, wherein one of R³and R⁴ is alkyl and the other one is alkyl or haloalkylcycloalkyl.
 7. Acompound according to claim 1, wherein one of R³ and R⁴ is methyl andthe other one is tert.-butyl or trifluoromethylcyclopropyl.
 8. Acompound according to claim 1, wherein R³ and R⁴ together with thenitrogen atom to which they are attached form heterocyclyl orsubstituted heterocyclyl, wherein heterocyclyl is oxazolidinyl,morpholinyl, pyrrolidinyl, 6-aza-bicyclo[3.2.1.]octyl,4-aza-spiro[2.4]heptyl, 2-thia-5-aza-bicyclo[2.2.1]heptyl,5-aza-spiro[3.4]octyl, 5-aza-spiro[2.4]heptyl,1,8-diaza-spiro[4.5]decyl, thiazolidinyl or 5-aza-spiro[2.4]heptyl, andwherein substituted heterocyclyl is heterocyclyl substituted with one tothree substituents independently selected from alkyl, hydroxyalkyl,halogen, aminocarbonyl, alkoxycarbonyl, oxo or hydroxyl.
 9. A compoundaccording to claim 1, wherein R³ and R⁴ together with the nitrogen atomto which they are attached form heterocyclyl or substitutedheterocyclyl, wherein heterocyclyl is oxazolidinyl, morpholinyl,pyrrolidinyl, 6-aza-bicyclo[3.2.1.]octyl, 4-aza-spiro[2.4]heptyl,2-thia-5-aza-bicyclo[2.2.1]heptyl, 5-aza-spiro[3.4]octyl,5-aza-spiro[2.4]heptyl, 1,8-diaza-spiro[4.5]decyl, thiazolidinyl or5-aza-spiro[2.4]heptyl, and wherein substituted heterocyclyl isheterocyclyl substituted with one to three substituents independentlyselected from methyl, hydroxymethyl, fluoro, aminocarbonyl,tert.-butoxycarbonyl, oxo or hydroxyl.
 10. A compound according to claim1, wherein R³ and R⁴ together with the nitrogen atom to which they areattached form dimethyloxazolidinyl, dimethylmorpholinyl,dimethylpyrrolidinyl, trimethyl-6-aza-bicyclo[3.2.1.]octyl,(hydroxymethyl)(difluoro)pyrrolidinyl, 4-aza-spiro[2.4]heptyl,(aminocarbonyl)(difluoro)pyrrolidinyl,2-thia-5-aza-bicyclo[2.2.1]heptyl,(aminocarbonyl)(dimethyl)pyrrolidinyl, 5-aza-spiro[3.4]octyl,difluoro-5-aza-spiro[2.4]heptyl, 5-aza-spiro[2.4]heptyl,tert.-butoxycarbonyl-1,8-diaza-spiro[4.5]decyl,aminocarbonyl-1,1-dioxo-1λ6-thiazolidinyl,aminocarbonyl-1,1-dioxo-1,3-thiazolidinyl,(aminocarbonyl)(methyl)(hydroxyl)pyrrolidinyl or(aminocarbonyl)-5-aza-spiro[2.4]heptyl.
 11. A compound according toclaim 1 selected from6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylicacid tert-butyl-methyl-amide;6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylicacid dimethylamide;5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acidtert-butyl-methyl-amide;5-Cyclopropyl-6-(tetrahydro-furan-2-ylmethoxy)-pyridine-2-carboxylicacid tert-butyl-methyl-amide;5-Cyclopropyl-6-(4-fluoro-benzyl)-pyridine-2-carboxylic acidtert-butyl-methyl-amide;5-Cyclopropyl-6-(2-methyl-propane-1-sulfonyl)-pyridine-2-carboxylic acidtert-butyl-methyl-amide;6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylicacid tert-butyl-ethyl-amide;6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylicacid diisopropylamide;6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylicacid (2-methoxy-1,1-dimethyl-ethyl)-methyl-amide;[6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridin-2-yl]-(6-oxa-1-aza-spiro[3.3]hept-1-yl)-methanone;[6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridin-2-yl]-(2-oxa-6-aza-spiro[3.3]hept-6-yl)-methanone;6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylicacid2-{[6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carbonyl]-methyl-amino}-2-methyl-propylester;5-Cyclopropyl-6-(2,2,2-trifluoro-1-methyl-ethoxy)-pyridine-2-carboxylicacid tert-butyl-methyl-amide;[6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridin-2-yl]-(4,4-dimethyl-oxazolidin-3-yl)-methanone;6-(Tetrahydro-furan-2-ylmethoxy)-5-trifluoromethyl-pyridine-2-carboxylicacid tert-butyl-methyl-amide;6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylicacid methyl-(1-trifluoromethyl-cyclopropyl)-amide;[6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridin-2-yl]-(3,3-dimethyl-morpholin-4-yl)-methanone;[6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridin-2-yl]-(2,2-dimethyl-pyrrolidin-1-yl)-methanone;6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylicacid (2-hydroxy-1,1-dimethyl-ethyl)-(2-methoxy-ethyl)-amide;6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylicacid tert-butyl-(2-methoxy-ethyl)-amide;6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylicacid ethyl-(1-trifluoromethyl-cyclopropyl)-amide;6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylicacid benzyl-(1-trifluoromethyl-cyclopropyl)-amide;{tert-Butyl-[6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carbonyl]-amino}-aceticacid ethyl ester;{tert-Butyl-[6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carbonyl]-amino}-aceticacid;6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylicacid benzyl-tert-butyl-amide;6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylicacid tert-butyl-methylcarbamoylmethyl-amide;6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylicacid tert-butyl-dimethylcarbamoylmethyl-amide;4-[6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carbonyl]-3,3-dimethyl-piperazin-2-one;4-[6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carbonyl]-3,3-diethyl-piperazin-2-one;[5-Cyclopropyl-6-(2-methyl-propane-1-sulfonyl)-pyridin-2-yl]-(2,2-dimethyl-pyrrolidin-1-yl)-methanone;[5-Cyclopropyl-6-(2-methyl-propane-1-sulfonyl)-pyridin-2-yl]-(4,4-dimethyl-oxazolidin-3-yl)-methanone;6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylicacid[(S)-2-cyclopropyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethyl]-methyl-amide;5-Cyclopropyl-6-(tetrahydro-pyran-4-ylmethoxy)-pyridine-2-carboxylicacid [cyclopropyl-(5-methyl-[1,2,4]oxadiazol-3-yl)-methyl]-methyl-amide;(+)-6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylicacid methyl-(3-methyl-1-pyridazin-3-yl-butyl)-amide;6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylicacid tert-butyl-carbamoylmethyl-amide;6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylicacid tert-butyl-(5-methyl-[1,3,4]oxadiazol-2-ylmethyl)-amide;[6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridin-2-yl]-(3-hydroxy-3-methyl-pyrrolidin-1-yl)-methanone;[6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridin-2-yl]-(2-oxa-5-aza-spiro[3.4]oct-5-yl)-methanone;6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylicacid ethyl-(2-methoxy-ethyl)-amide;6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylicacid tert-butyl-(1-methyl-1H-tetrazol-5-ylmethyl)-amide;N-{1-[6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carbonyl]-pyrrolidin-3-yl}-acetamide;[5-Cyclopropyl-6-(4-fluoro-benzyl)-pyridin-2-yl]-(4,4-dimethyl-piperidin-1-yl)-methanone;[5-Cyclopropyl-6-(tetrahydro-furan-2-ylmethoxy)-pyridin-2-yl]-(4,4-dimethyl-piperidin-1-yl)-methanone;[5-Cyclopropyl-6-(4-fluoro-benzyl)-pyridin-2-yl]-(4,4-dimethyl-oxazolidin-3-yl)-methanone;[6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridin-2-yl]-((1S,5R)-1,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct-6-yl)-methanone;[6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridin-2-yl]-((R)-2-methoxymethyl-pyrrolidin-1-yl)-methanone;(6-Chloro-5-cyclopropylmethoxy-pyridin-2-yl)-(2,2-dimethyl-pyrrolidin-1-yl)-methanone;(6-Cyclopropylmethoxy-5-trifluoromethoxy-pyridin-2-yl)-(4,4-dimethyl-oxazolidin-3-yl)-methanone;(6-Chloro-5-cyclopropylmethoxy-pyridin-2-yl)-(4,4-dimethyl-oxazolidin-3-yl)-methanone;6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylicacid (1-acetyl-piperidin-4-yl)-cyclopropyl-amide;6-(Cyclopropylmethoxy)-5-(3,3-difluoroazetidin-1-yl)-N-formyl-N-methylpyridine-2-carboxamide;6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylicacid methyl-phenyl-amide;[6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridin-2-yl]-((S)-4,4-difluoro-2-hydroxymethyl-pyrrolidin-1-yl)-methanone;6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylicacid (1,4-dimethyl-1H-pyrazol-3-yl)-methyl-amide;[6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridin-2-yl]-(2,2-dimethyl-morpholin-4-yl)-methanone;(R)-2-tert-Butyl-1-[6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carbonyl]-3-methyl-imidazolidin-4-one;(4-Aza-spiro[2.4]hept-4-yl)-[6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridin-2-yl]-methanone;3-{1-[6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carbonyl]-piperidin-4-yl}-5,5-dimethyl-pyrrolidin-2-one;(1S,4R)-2-Aza-bicyclo[2.2.1]hept-2-yl-[6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridin-2-yl]-methanone;(S)-1-[6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carbonyl]-4,4-difluoro-pyrrolidine-2-carboxylicacid amide;[6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridin-2-yl]-(4-hydroxy-4-methyl-piperidin-1-yl)-methanone;[6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridin-2-yl]-(1S,4S)-2-thia-5-aza-bicyclo[2.2.1]hept-5-yl-methanone;((1S,4S)-5-Benzyl-2,5-diaza-bicyclo[2.2.1]hept-2-yl)-[6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridin-2-yl]-methanone;[6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridin-2-yl]-(2-methyl-3-phenyl-piperidin-1-yl)-methanone;[6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridin-2-yl]-(1S,4S)-2-oxa-5-aza-bicyclo[2.2.1]hept-5-yl-methanone;[6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridin-2-yl]-(4-hydroxy-2,2-dimethyl-piperidin-1-yl)-methanone;1-[6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carbonyl]-2-phenylpiperidine-3-carboxylicacid ethyl ester;(S)-1-(5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carbonyl)-4,4-difluoro-pyrrolidine-2-carboxylicacid amide;(2S,4S)-1-(5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carbonyl)-4-fluoro-pyrrolidine-2-carboxylicacid amide;[6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridin-2-yl]-(hexahydro-furo[2,3-c]pyrrol-5-yl)-methanone;[6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridin-2-yl]-(2,2-dioxo-2λ6-thia-6-aza-spiro[3.3]hept-6-yl)-methanone;6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylicacid tert-butyl-(2-carbamoyl-ethyl)-amide;(S)-1-(5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carbonyl)-pyrrolidine-2-carboxylicacid amide;1-[6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carbonyl]-1,8-diaza-spiro[4.5]decane-8-carboxylicacid tert-butyl ester;(S)-1-{5-Cyclopropyl-6-[(R,S)-1-(tetrahydro-furan-2-yl)methoxy]-pyridine-2-carbonyl}-4,4-difluoro-pyrrolidine-2-carboxylicacid amide;(S)-1-[5-Cyclopropyl-6-(4-fluoro-benzyl)-pyridine-2-carbonyl]-4,4-difluoro-pyrrolidine-2-carboxylicacid amide;(+)-1-[6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carbonyl]-4,4-dimethyl-pyrrolidine-2-carboxylicacid amide;(−)-1-[6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carbonyl]-4,4-dimethyl-pyrrolidine-2-carboxylicacid amide;(2S,4S)-1-[6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carbonyl]-4-hydroxy-pyrrolidine-2-carboxylicacid amide;(2S,4S)-1-[6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carbonyl]-4-fluoro-pyrrolidine-2-carboxylicacid amide;6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylicacid cyclopropyl-(5-methyl-[1,3,4]oxadiazol-2-ylmethyl)-amide;[6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridin-2-yl]-(3-hydroxy-1-oxa-7-aza-spiro[4.4]non-7-yl)-methanone;[6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridin-2-yl]-(7-hydroxy-5-oxa-2-aza-spiro[3.4]oct-2-yl)-methanone;[5-Cyclopropyl-6-(2,2,3,3,3-pentafluoro-propoxy)-pyridin-2-yl]-(2,2-dimethyl-pyrrolidin-1-yl)-methanone;[6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridin-2-yl]-(1S,5R)-8-oxa-3-aza-bicyclo[3.2.1]oct-3-yl-methanone;[6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridin-2-yl]-(1R,5S)-3-oxa-8-aza-bicyclo[3.2.1]oct-8-yl-methanone;(R)-1-[5-Cyclopropyl-6-(2,2,3,3,3-pentafluoro-propoxy)-pyridine-2-carbonyl]-4,4-difluoro-pyrrolidine-2-carboxylicacid amide;1-(5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carbonyl)-piperidine-2-carboxylicacid amide;4-(5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carbonyl)-thiomorpholine-3-carboxylicacid amide;1-(5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carbonyl)-4,4-dimethyl-pyrrolidine-2-carboxylicacid amide;(+)-1-(5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carbonyl)-piperidine-2-carboxylicacid amide;(−)-1-(5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carbonyl)-piperidine-2-carboxylicacid amide;(−)-4-(5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carbonyl)-thiomorpholine-3-carboxylicacid amide;(+)-1-(5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carbonyl)-4,4-dimethyl-pyrrolidine-2-carboxylicacid amide;(−)-1-(5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carbonyl)-4,4-dimethyl-pyrrolidine-2-carboxylicacid amide;3-(5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carbonyl)-thiazolidine-4-carboxylicacid amide;(−)-3-(5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carbonyl)-thiazolidine-4-carboxylicacid amide;1-[6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carbonyl]-4,4-dimethyl-pyrrolidine-2-carboxylicacid amide;[6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridin-2-yl]-(5-oxa-2-aza-spiro[3.4]oct-2-yl)-methanone;[6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridin-2-yl]-(1-oxa-7-aza-spiro[4.4]non-7-yl)-methanone;(5-Aza-spiro[3.4]oct-5-yl)-[6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridin-2-yl]-methanone;[6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridin-2-yl]-(3,3-difluoro-azetidin-1-yl)-methanone;[6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridin-2-yl]-(1,1-difluoro-5-aza-spiro[2.4]hept-5-yl)-methanone;(5-Aza-spiro[2.4]hept-5-yl)-[6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridin-2-yl]-methanone;6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylicacid cyclopropylmethyl-methyl-amide;[6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridin-2-yl]-(4-cyclopropylmethyl-piperazin-1-yl)-methanone;3-[6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carbonyl]-3-aza-bicyclo[3.1.0]hexane-6-carboxylicacid ethyl ester;1-[6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carbonyl]-pyrrolidine-2-carboxylicacid methyl ester;4-[6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carbonyl]-piperazine-1-carboxylicacid benzyl ester;3-[6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carbonyl]-3-aza-bicyclo[3.1.0]hexane-6-carboxylicacid;1-[5-Cyclopropyl-6-(4-fluoro-benzyl)-pyridine-2-carbonyl]-1,8-diaza-spiro[4.5]decane-8-carboxylicacid tert-butyl ester;(−)-3-[6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carbonyl]-thiazolidine-4-carboxylicacid amide;[5-Cyclopropyl-6-(4-fluoro-benzyl)-pyridin-2-yl]-(1,8-diaza-spiro[4.5]dec-1-yl)-methanone;1-[6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carbonyl]-pyrrolidine-2-carboxylicacid amide;(−)-3-(5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carbonyl)-1,1-dioxo-1λ6-thiazolidine-4-carboxylicacid amide;(1S,4R)-3-(5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carbonyl)-1-oxo-1λ4-thiazolidine-4-carboxylicacid amide;(1R,4S)-3-(5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carbonyl)-1-oxo-1λ4-thiazolidine-4-carboxylicacid amide;(+)-3-(5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carbonyl)-1,1-dioxo-1λ6-thiazolidine-4-carboxylicacid amide;[6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridin-2-yl]-(3,3,4,4-tetrafluoro-pyrrolidin-1-yl)-methanone;[6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridin-2-yl]-(2,6-dimethyl-morpholin-4-yl)-methanone;(R)-3-[6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carbonyl]-5,5-dimethyl-thiazolidine-4-carboxylicacid amide;(S)-1-[6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carbonyl]-5,5-dimethyl-pyrrolidine-2-carboxylicacid amide;3-[6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carbonyl]-thiazolidine-4-carboxylicacid amide;(2S,4R)-1-[5-Cyclopropyl-6-(cyclopropylmethoxy)pyridine-2-carbonyl]-4-fluoropyrrolidine-2-carboxamide;3-[6-(Cyclopropylmethoxy)-5-(3,3-difluoroazetidin-1-yl)pyridine-2-carbonyl]-1-oxo-1,3-thiazolidine-4-carboxamide;3-[6-(Cyclopropylmethoxy)-5-(3,3-difluoroazetidin-1-yl)pyridine-2-carbonyl]-1,1-dioxo-1,3-thiazolidine-4-carboxamide;(2S,4R)-1-[6-(Cyclopropylmethoxy)-5-(3,3-difluoroazetidin-1-yl)pyridine-2-carbonyl]-4-fluoropyrrolidine-2-carboxamide;(−)-3-[6-(Cyclopropylmethoxy)-5-(3,3-difluoroazetidin-1-yl)pyridine-2-carbonyl]-1,1-dioxo-1,3-thiazolidine-4-carboxamide;3-[6-(Cyclopropylmethoxy)-5-(3-methoxyazetidin-1-yl)pyridine-2-carbonyl]-1,1-dioxo-1,3-thiazolidine-4-carboxamide;(2S)-1-[6-(Cyclopropylmethoxy)-5-(1-hydroxycyclobutyl)pyridine-2-carbonyl]-4,4-difluoropyrrolidine-2-carboxamide;(2S)-1-[6-(Cyclopropylmethoxy)-5-(1-fluorocyclobutyl)pyridine-2-carbonyl]-4,4-difluoropyrrolidine-2-carboxamide;3-[6-(Cyclopropylmethoxy)-5-(1-hydroxycyclobutyl)pyridine-2-carbonyl]-1,1-dioxo-1,3-thiazolidine-4-carboxamide;(2S)-1-[6-(Cyclopropylmethoxy)-5-(3,3-difluoroazetidin-1-yl)pyridine-2-carbonyl]-4-hydroxy-4-methylpyrrolidine-2-carboxamide;3-[6-(Cyclopropylmethoxy)-5-(1-fluorocyclobutyl)pyridine-2-carbonyl]-1,1-dioxo-1,3-thiazolidine-4-carboxamide;(2S)-1-[6-(Cyclopropylmethoxy)-5-(3-fluorooxetan-3-yl)pyridine-2-carbonyl]-4,4-difluoropyrrolidine-2-carboxamide;5-[6-(Cyclopropylmethoxy)-5-(3,3-difluoroazetidin-1-yl)pyridine-2-carbonyl]-5-azaspiro[2.4]heptane-6-carboxamide;[6-(Cyclopropylmethoxy)-5-(3,3-difluoroazetidin-1-yl)pyridin-2-yl]-[3-(2,2,2-trifluoro-1-hydroxyethyl)pyrrolidin-1-yl]methanone;[6-(Cyclopropylmethoxy)-5-(3,3-difluoroazetidin-1-yl)pyridin-2-yl]-[3-(hydroxymethyl)-3-(trifluoromethyl)pyrrolidin-1-yl]methanone;[6-(Cyclopropylmethoxy)-5-(3,3-difluoroazetidin-1-yl)pyridin-2-yl]-[3-hydroxy-3-(trifluoromethyl)pyrrolidin-1-yl]methanone;[6-(Cyclopropylmethoxy)-5-(3,3-difluoroazetidin-1-yl)pyridin-2-yl]-[3-hydroxy-3-(trifluoromethyl)azetidin-1-yl]methanone;(+)-(2S)-1-[6-(Cyclopropylmethoxy)-5-(3,3-difluoroazetidin-1-yl)pyridine-2-carbonyl]-4-hydroxy-4-methylpyrrolidine-2-carboxamide;[5-Cyclopropyl-6-(cyclopropylmethoxy)pyridin-2-yl]-[3-(2,2,2-trifluoro-1-hydroxyethyl)pyrrolidin-1-yl]methanone;[5-Cyclopropyl-6-(cyclopropylmethoxy)pyridin-2-yl]-[3-(hydroxymethyl)-3-(trifluoromethyl)pyrrolidin-1-yl]methanone;[5-Cyclopropyl-6-(cyclopropylmethoxy)pyridin-2-yl]-[3-hydroxy-3-(trifluoromethyl)pyrrolidin-1-yl]methanone;[5-Cyclopropyl-6-(cyclopropylmethoxy)pyridin-2-yl]-[3-hydroxy-3-(trifluoromethyl)azetidin-1-yl]methanone;(6S)-5-[6-(Cyclopropylmethoxy)-5-(3,3-difluoroazetidin-1-yl)pyridine-2-carbonyl]-5-azaspiro[2.4]heptane-6-carboxamide;[(3aR,6aS)-1,3,3a,4,6,6a-Hexahydrofuro[3,4-c]pyrrol-5-yl]-[6-(cyclopropylmethoxy)-5-(3,3-difluoroazetidin-1-yl)pyridin-2-yl]methanone;(2S)-1-[5-(3,3-Difluoroazetidin-1-yl)-6-(2-fluoroethoxy)pyridine-2-carbonyl]-4,4-difluoro-pyrrolidine-2-carboxamide;[6-(Cyclopropylmethoxy)-5-(3,3-difluoroazetidin-1-yl)-2-pyridyl]-[3-fluoro-3-(hydroxymethyl)azetidin-1-yl]methanone;[6-(Cyclopropylmethoxy)-5-(3,3-difluoroazetidin-1-yl)-2-pyridyl]-(3-fluoro-3-methyl-azetidin-1-yl)methanone;(3-Cyclopropyl-3-fluoroazetidin-1-yl)-[6-(cyclopropylmethoxy)-5-(3,3-difluoroazetidin-1-yl)pyridin-2-yl]methanone;(−)-5-[6-(Cyclopropylmethoxy)-5-(3,3-difluoroazetidin-1-yl)pyridine-2-carbonyl]-5-azaspiro[2.4]heptane-4-carboxamide;and(+)-5-[6-(Cyclopropylmethoxy)-5-(3,3-difluoroazetidin-1-yl)pyridine-2-carbonyl]-5-azaspiro[2.4]heptane-4-carboxamide.12. A compound according to claim 1 selected from6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylicacid tert-butyl-methyl-amide;5-Cyclopropyl-6-(tetrahydro-furan-2-ylmethoxy)-pyridine-2-carboxylicacid tert-butyl-methyl-amide;[6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridin-2-yl]-(4,4-dimethyl-oxazolidin-3-yl)-methanone;6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylicacid methyl-(1-trifluoromethyl-cyclopropyl)-amide;[6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridin-2-yl]-(3,3-dimethyl-morpholin-4-yl)-methanone;[5-Cyclopropyl-6-(2-methyl-propane-1-sulfonyl)-pyridin-2-yl]-(2,2-dimethyl-pyrrolidin-1-yl)-methanone;[5-Cyclopropyl-6-(4-fluoro-benzyl)-pyridin-2-yl]-(4,4-dimethyl-oxazolidin-3-yl)-methanone;[6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridin-2-yl]-((1S,5R)-1,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct-6-yl)-methanone;[6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridin-2-yl]-((S)-4,4-difluoro-2-hydroxymethyl-pyrrolidin-1-yl)-methanone;(4-Aza-spiro[2.4]hept-4-yl)-[6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridin-2-yl]-methanone;[6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridin-2-yl]-(1S,4S)-2-thia-5-aza-bicyclo[2.2.1]hept-5-yl-methanone;(S)-1-(5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carbonyl)-4,4-difluoro-pyrrolidine-2-carboxylicacid amide;(−)-1-[6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carbonyl]-4,4-dimethyl-pyrrolidine-2-carboxylicacid amide;(5-Aza-spiro[3.4]oct-5-yl)-[6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridin-2-yl]-methanone;[6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridin-2-yl]-(1,1-difluoro-5-aza-spiro[2.4]hept-5-yl)-methanone;(5-Aza-spiro[2.4]hept-5-yl)-[6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridin-2-yl]-methanone;1-[5-Cyclopropyl-6-(4-fluoro-benzyl)-pyridine-2-carbonyl]-1,8-diaza-spiro[4.5]decane-8-carboxylicacid tert-butyl ester;(−)-3-(5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carbonyl)-1,1-dioxo-1λ6-thiazolidine-4-carboxylicacid amide;3-[6-(Cyclopropylmethoxy)-5-(3,3-difluoroazetidin-1-yl)pyridine-2-carbonyl]-1,1-dioxo-1,3-thiazolidine-4-carboxamide;(−)-3-[6-(Cyclopropylmethoxy)-5-(3,3-difluoroazetidin-1-yl)pyridine-2-carbonyl]-1,1-dioxo-1,3-thiazolidine-4-carboxamide;(2S)-1-[6-(Cyclopropylmethoxy)-5-(1-hydroxycyclobutyl)pyridine-2-carbonyl]-4,4-difluoropyrrolidine-2-carboxamide;(2S)-1-[6-(Cyclopropylmethoxy)-5-(1-fluorocyclobutyl)pyridine-2-carbonyl]-4,4-difluoropyrrolidine-2-carboxamide;(2S)-1-[6-(Cyclopropylmethoxy)-5-(3,3-difluoroazetidin-1-yl)pyridine-2-carbonyl]-4-hydroxy-4-methylpyrrolidine-2-carboxamide;3-[6-(Cyclopropylmethoxy)-5-(1-fluorocyclobutyl)pyridine-2-carbonyl]-1,1-dioxo-1,3-thiazolidine-4-carboxamide;and5-[6-(Cyclopropylmethoxy)-5-(3,3-difluoroazetidin-1-yl)pyridine-2-carbonyl]-5-azaspiro[2.4]heptane-6-carboxamide.13. A process for the preparation of a compound of claim 1 comprisingone of the following steps: (a) the reaction of a compound of formula(A)

in the presence of NHR³R⁴, an amide bond forming coupling agent and abase; or (b) the reaction of a compound of formula (B)

with a compound of formula R⁴—X; wherein R¹ to R⁴ are as defined inclaim 1 and X is a leaving group.
 14. A compound manufactured accordingto a process of claim
 13. 15. A pharmaceutical composition comprising acompound of claim 1 and a therapeutically inert carrier.
 16. A methodfor the treatment of pain, atherosclerosis, age-related maculardegeneration, diabetic retinopathy, glaucoma, retinal vein occlusion,retinopathy of prematurity, ocular ischemic syndrome, geographicatrophy, diabetes mellitus, inflammation, inflammatory bowel disease,ischemia-reperfusion injury, acute liver failure, liver fibrosis, lungfibrosis, kidney fibrosis, systemic fibrosis, acute allograft rejection,chronic allograft nephropathy, diabetic nephropathy,glomerulonephropathy, cardiomyopathy, heart failure, myocardialischemia, myocardial infarction, systemic sclerosis, thermal injury,burning, hypertrophic scars, keloids, gingivitis pyrexia, livercirrhosis or tumors, regulation of bone mass, neurodegeneration,amyotrophic lateral sclerosis, stroke, transient ischemic attack oruveitis, which method comprises administering an effective amount of acompound of claim 1 to a patient in need thereof.